Special Report
`
`Concern over Zika virus grips the world
`In the past week, the world has mobilised to tackle the latest threat to global health security—
`Zika virus, now spreading rapidly in the Americas. Udani Samarasekera and Marcia Triunfol report.
`
`CDC/Science Photo Library
`
`Published Online
`February 2, 2016
`http://dx.doi.org/10.1016/
`S0140-6736(16)00257-9
`
`For The Lancet’s Zika virus
`Resource Centre see www.
`thelancet.com/campaigns/zika
`
`Chile), an area encompassing around
`500 million people.
`WHO estimates that there will be
`3–4 million cases of Zika infection
`(including asymptomatic cases) in
`the Americas in the next 12 months.
`The fi gure comes from mathematical
`modelling based on dengue dynamics
`in the region and Zika infections in
`Brazil. An estimated 2 million cases
`of dengue occurred in the Americas
`in 2015. But unlike the dengue virus,
`which has been circulating in the
`region since the 1980s, Zika is new
`to the Americas and it is circulating
`at a very high intensity. The Brazil
`Ministry of Health estimates that
`440 000–1 300 000 sus pected cases
`of Zika virus infection occurred in the
`country in 2015.
`In the Jan 28 briefi ng, Bruce Aylward,
`Assistant Director-General, WHO,
`advised that “any country in the dengue
`belt that has Aedes aegypti should
`
`Panel: Zika virus
`
`Zika virus is an arbovirus of the Flaviviridae family, which includes
`dengue, West Nile, yellow fever, and Japanese encephalitis viruses.
`Like other members of the genus, Zika virus contains a positive,
`single-stranded genomic RNA encoding a polyprotein.
`
`Zika virus was fi rst isolated in 1947 from a rhesus monkey in the
`Zika forest of Uganda. Transmitted by the Aedes genus of
`mosquito, for decades, the disease mainly aff ected monkeys in a
`narrow equatorial belt stretching across Africa and into equatorial
`Asia. It occasionally aff ected human beings causing a mild disease.
`
`In 2007, the fi rst documented outbreak of Zika occurred in the
`Federated States of Micronesia where 185 suspected cases were
`reported, of which 49 were confi rmed and 59 were considered
`probable. Between 2013 and 2014, four additional Pacifi c Island
`nations documented large Zika outbreaks. In French Polynesia, the
`Zika outbreak was associated with neurological complications, but
`at a time when the virus was co-circulating with dengue.
`
`In May, 2015, WHO confi rmed the presence of Zika virus in the
`Americas. As of Feb 1, 2016, active transmission has been reported
`in 28 coun tries and territories, mainly in the Americas, but also in
`Africa (Cape Verde) and Oceania (American Samoa, Samoa).
`
`521
`
`Zika
`over
`concern
`Worldwide
`virus (panel) and its temporal and
`geographical association with clusters
`of birth and neurological conditions
`escalated
`this week, with WHO
`declaring a Public Health Emergency
`of International Concern.
`No doubt not wanting to repeat
`mistakes made in the west African
`Ebola outbreak, WHO was quick to raise
`the alarm. Briefi ng the WHO Executive
`Board on Jan 28, WHO Director-
`General Margaret Chan said Zika virus,
`now “spreading explosively” in the
`Americas, was deeply concerning for
`the organisation. Although a causal
`relation between infection with the
`virus and birth malformations and
`neurological syndromes has not been
`established, it is strongly suspected,
`Chan noted. “The possible links…have
`rapidly changed the risk profi le of Zika,
`from a mild threat to one of alarming
`proportions. The increased incidence of
`microcephaly is particularly alarming,
`as it places a heart-breaking burden on
`families and communities.”
`She told the Executive Board
`that the concerns about Zika
`warranted convening an Emergency
`Committee under the International
`Health Regulations to advise on the
`appropriate level of international
`concern, recommend measures that
`should be undertaken in affected
`countries and elsewhere, and prioritise
`areas where research is most urgently
`needed. “The level of concern is high,
`as is the level of uncertainty. Questions
`abound. We need to get some answers
`quickly”, she said.
`The Emergency Committee met
`on Feb 1 and concluded that the
`recent cluster of microcephaly cases
`and other neurological disorders
`reported in Brazil, following a similar
`cluster in French Polynesia in 2014,
`was an “extraordinary event” and
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`www.thelancet.com Vol 387 February 6, 2016
`
`constituted a Public Health Emergency
`of International Concern.
`On Feb 1, Chan said that WHO
`had accepted the committees’
`recommendation. She explained that
`declaring an emergency would allow
`for a coordinated global eff ort to get
`underway, enabling surveillance for
`microcephaly to be standardised and
`research to be intensified. Chan said
`that there was no reason to introduce
`restrictions to travel or trade, but
`
`“‘...any country in the dengue
`belt that has Aedes aegypti
`should be looking at whether
`there is Zika and put in place
`measures to detect neurological
`conditions’.”
`
`pregnant women could consider
`delaying travel to affected areas or
`seek advice from their physician if they
`needed to travel and take precautionary
`measures against infection.
`
`At-risk population
`As of Feb 1, 2016, active transmission
`of Zika virus was being reported in
`28 countries and territories (fi gure),
`mostly in the Americas, including
`Brazil, Colombia, Venezuela, Mexico,
`Haiti, and Barbados. Sylvain Aldighieri,
`head of
`International Health
`Regulations Epidemic Alert and
`Response at the Pan American Health
`Organization (PAHO), explained
`to reporters in a WHO briefing on
`Jan 28 that the fast dissemination
`of the virus in the Americas was
`down to two reasons: the population
`being immunologically naive to Zika
`virus and the ubiquitous presence of
`the vector—Aedes mosquitoes. The
`vector can be found in the region
`from southern USA to northern
`Argentina (excluding continental
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`Takeda EX1070
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`Special Report
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`the country after the Zika outbreak,
`Aylward noted. However, both Brazil
`and French Polynesia have also
`experienced outbreaks of dengue and
`chikungunya, raising the possibility of
`co-infections.
`
`Research pipeline
`Aylward said that four types of studies
`were underway to try to answer
`some of the many questions about
`the Zika virus: case investigations
`and ecological, case-control, and
`cohort studies. He noted that
`Marie-Paule Kieny, WHO Assistant
`Director-General for Health Systems
`and Innovation, was leading a scoping
`exercise to assess the research—
`including diagnostics and vaccine
`research—being done worldwide.
`“Within a couple of weeks, WHO
`will have a good idea of where we
`are, what the research pipeline is”,
`said Aylward. This knowledge will
`help the agency assess the merit of
`an accelerated agenda for product
`development. However, Aylward
`cautioned that a vaccine might not be
`available any time soon, noting that
`the timeframe for a dengue vaccine
`was many years.
`In a briefi ng organised by the CDC
`on Jan 28, Anthony Fauci, Director
`of the National Institutes for Allergy
`and Infectious Diseases (NIAID) at the
`National Institutes of Health (NIH),
`outlined the NIH’s plans. “Within NIH,
`we have long supported research on
`viruses…With the emergence of the
`Zika virus, we are focusing eff orts on
`several fronts”, he said, including the
`development of animal models.
`“We are also supporting, along
`with the CDC, the development of
`diagnostic platforms that can rapidly
`determine if a patient is infected
`with Zika or has been infected either
`recently or in the past, and distinguish
`it from other viruses, particularly
`dengue infection. Such diagnostic
`tools will be critical to reassure the
`unaff ected pregnant women in areas
`where Zika is occurring and pregnant
`women returning from such areas.”
`
`www.thelancet.com Vol 387 February 6, 2016
`
`Americas
`Barbados
`Bolivia
`Brazil
`Colombia
`Costa Rica
`Curacao
`Dominican Republic
`Ecuador
`El Salvador
`French Guiana
`
`Guadeloupe
`Guatemala
`Guyana
`Haiti
`Honduras
`Martinique
`Mexico
`Nicaragua
`Panama
`Paraguay
`Puerto Rico
`
`Saint Martin
`Suriname
`US Virgin Islands
`Venezuela
`
`Oceania/Pacific Islands
`American Samoa
`Samoa
`
`Africa
`Cape Verde
`
`Reported active transmission
`
`Source: US Centers for Disease Control and Prevention
`
`Figure: Countries and territories reporting active Zika virus transmission as of Feb 1, 2016
`
`be looking at whether there is Zika
`and put in place measures to detect
`neurological conditions”.
`He said that WHO would not be
`giving advice to women, as some
`countries in the Americas have, about
`delaying pregnancy, but it would give
`advice about how they can lower their
`risk of infection. On WHO’s website
`that advice (as for any mosquito-
`borne disease) is: use insect repellent;
`cover as much of the body as possible
`with long, light-coloured clothing;
`empty, clean, or cover containers
`that can hold water to remove places
`mosquitoes can breed; and sleep under
`mosquito nets.
`
`Health concerns
`Most people infected with Zika virus
`will not show any clear symptoms.
`However, in about one in fi ve people,
`Zika causes a mild disease, with
`symptoms lasting from several days to
`a week. The most common symptoms
`are fever, rash,
`joint pain, and
`conjunctivitis. Severe disease requiring
`admission to hospital is uncommon.
`The major concern in the present
`outbreak is related to the microcephaly
`clusters in Brazil, which have captured
`the attention of not only WHO
`but also the world’s media. During
`October and November, 2015, the
`Ministry of Health in Brazil began
`reporting an unusual increase in cases
`of microcephaly, fi rst, in the state of
`
`Pernambuco, located in the northeast
`of Brazil, then in three other states. On
`Nov 11, Brazil declared the situation a
`national public health emergency and
`began undertaking clinical, laboratory,
`and ultrasound analysis of affected
`newborn babies and their mothers.
`On Nov 17, WHO and PAHO issued an
`epidemiological alert, calling upon
`Member States to remain alert to
`the occurrence of similar events in
`their territories and to notify their
`occurrence through the channels
`established under the International
`Health Regulations.
`Health authorities in Brazil have
`also reported an unusual increase
`in Guillain-Barré syndrome. The
`US Centers for Disease Control and
`Prevention (CDC) is currently working
`with public health officials in the
`country to investigate whether there is
`any link between Zika infection and the
`rare neurological disorder.
`The other country to have seen
`similar neurological events in a Zika
`outbreak is French Polynesia. At
`the end of October, 2013, around
`10 000 infections were registered
`in the Pacific Island nation, around
`70 of which were severe cases,
`including neurological (Guillain-Barré
`syndrome, meningoencephalitis) or
`autoimmune (thrombocytopenic
`purpura, leucopenia) complications.
`Retrospectively, there were a small
`number of microcephaly cases in
`
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`Special Report
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`523
`
`Mario Tama
`
`that suspected cases of Zika-related
`microcephaly be reported using this
`form. However, in another document
`issued
`in November, 2015, the
`Ministry of Health said that all cases
`of microcephaly should be reported in
`the RESP form.
`This conflicting information has
`resulted in health authorities in
`each state developing their own
`interpretation of which system to
`use and how. For instance, the state
`of São Paulo, one of the largest in
`the country, only reports in the RESP
`registry microcephaly cases in which
`some evidence of a connection with
`infection by Zika is established.
`Meanwhile, Alexandre Chieppe,
`superintendent of Environmental
`and Epidemiological Surveillance,
`State Secretary of Health, Rio de
`Janeiro, said that in the state of Rio
`de Janeiro, all cases of microcephaly,
`regardless of any connection with Zika,
`are notified in the RESP system. He
`explained that “a potential connection
`between microcephaly and infection
`by Zika during pregnancy depends
`on a comprehensive investigation
`that is done by a team of doctors and
`that requires a number of exams and
`analyses done later on”.
`
`Pernambuco
`In Brazil, microcephaly was initially
`defi ned as head circumference below
`33 cm and later corrected to 32 cm.
`In the state of Pernambuco, although
`1373 cases have been notified, only
`248 have been investigated and
`138 confirmed as microcephaly
`associated with some
`infectious
`aetiology, which may or may not
`
`He noted that researchers at NIAID
`are working on vaccine candidates
`to prevent Zika virus
`infection.
`Approaches being pursued include a
`DNA-based vaccine strategy, similar
`to the one used to develop a vaccine
`candidate against West Nile virus.
`NIAID was also evaluating a live-
`vaccine approach, similar to the
`strategy used to develop a vaccine
`against dengue virus. However,
`echoing Aylward’s sentiments, Fauci
`cautioned that “while these approaches
`are promising, it is important to
`understand we will not have a widely
`available safe and eff ective Zika vaccine
`this year and probably not in the next
`few years; although, we may be able
`to begin an early phase 1 clinical trial
`actually within this calendar year”.
`NIH has also issued a call to the
`research community to highlight
`its interest in funding a number of
`areas of research on Zika. In addition
`to accelerated research towards
`diagnostics, treatments, and vaccines,
`it is calling for basic research to
`understand Zika virus infection. NIH
`is already studying the evolution and
`emergence of the virus, and is planning
`studies of the pathogen’s distribution
`and natural history in collaboration
`with the CDC. “NIH is actively pursuing
`answers to the numerous scientific
`questions related to Zika infection,
`and we are sharing this information
`in real time, refi ning our avenues for
`accelerating research”, Fauci said.
`Brazil’s Ministry of Health has said
`that plans to develop a vaccine are also
`underway in the country. According
`to Pedro Vasconcelos, a doctor and
`researcher at Instituto Evandro Chagas,
`one of the three institutes in the
`country involved in the project, the
`vaccine will take 3–5 years to develop.
`The work is planned to start in February
`and will be done in collaboration with
`the University of Texas Medical Branch
`in Galveston, USA.
`Speaking to The Lancet, Trudie Lang,
`head of the Global Health Network—a
`forum to help clinical researchers with
`trials—said that a digital platform for
`
`www.thelancet.com Vol 387 February 6, 2016
`
`Zika research (www.zikainfection.
`tghn.org) has been launched by the
`International Severe Acute Respiratory
`and Emerging Infection Consortium
`and its international partners. “This is a
`resource that has been set up to enable
`research to get underway as quickly
`as possible. Here research tools and
`documents are being openly shared
`in order that studies can start as soon
`as possible and everyone collects data
`in the same way, so that it can then be
`pooled and shared.”
`Such an approach is important
`because there are many research
`questions that need to be answered
`quickly, she said.
`
`Reporting problems
`According to the latest epidemiological
`report by health authorities in Brazil,
`4180 cases of microcephaly have been
`reported between November, 2015,
`and the third week of January, 2016.
`The northeast region has the highest
`number of notifi ed cases, accounting
`for almost 80%, with Pernambuco
`reporting more than any other state.
`However, some scientists in Brazil
`believe that the increase is not as
`high as it seems and might be even
`smaller when considering only those
`cases associated with Zika infection.
`Mauro de Freitas Rebelo, a professor
`and researcher at the Environmental
`and Molecular Biology Lab at the
`Federal University of Rio de Janeiro,
`for example, thinks that the fact that
`notification became mandatory in
`2015 adds a bias that overestimates
`the increased rate of microcephaly in
`Brazil in the past year.
`Additional problems lie in the
`fact that there are two different
`notification systems to
`report
`microcephaly cases in Brazil. The
`official notification system for all
`babies born in the country—SINESC—
`proved too complex to report
`cases of microcephaly during the
`outbreak. To expedite notification,
`the Ministry of Health developed
`a new form—Registry of Events in
`Public Health (RESP)—and advised
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`Special Report
`
`department at the Ministry of Health,
`has stated that now is not a good time
`to get pregnant in high-risk areas.
`There are initial reports that panic is
`spreading among pregnant women,
`with some wanting an abortion if
`they get infected by Zika during the
`first months of gestation. Abortion
`in Brazil is legal only in cases where
`pregnancy represents a risk for the
`life of the mother or is the result
`of rape. The law also allows for
`abortion when it is confi rmed that the
`newborn will have a severe disease
`or congenital malformation. Because
`the link between Zika infection and
`microcephaly has not been confi rmed,
`and the diagnosis of microcephaly can
`only be determined in the last weeks of
`pregnancy, at birth, or even later, some
`pregnant women infected with Zika
`have sought abortion illegally.
`
`Losing battle
`The Brazilian Government has launched
`several campaigns to mobilise the
`population against the mosquito and
`has deployed military forces to visit all
`households in the country to educate
`people on vector control. However, this
`strategy does not seem to be working
`and the Health Minister Marcelo
`Castro and the Brazilian President
`Dilma Rousseff have both announced
`that the country is losing the battle
`against the mosquito. Many experts
`believe that the population is not
`doing its part in stopping mosquitoes
`breeding in stagnant water, others say
`that there is little the population can
`actually do and that the government
`needs to invest in research projects to
`eradicate the mosquito. Strategies such
`as the releasing of Wolbachia-infected
`A aegypti mosquitoes have been done
`in Brazil since 2014 in a few small areas
`but no results have been announced.
`As the world mobilises to answer the
`questions surrounding the Zika virus
`and congenital neurological conditions,
`Brazil is one country hoping that the
`answers will come soon.
`
`Udani Samarasekera, Marcia Triunfol
`
`www.thelancet.com Vol 387 February 6, 2016
`
`A health worker fumigates an area in Salvador, Bahía, Brazil on Jan 29, 2016
`
`include Zika. Patricia Ismael Carvalho,
`director general of Information and
`Strategic Actions for Epidemiological
`Surveillance at
`the State of
`Pernambuco Health Department,
`noted that the high number of
`microcephaly notifications in the
`state may result from the fact that
`Pernambuco was the fi rst to report on
`cases of microcephaly and therefore
`included a number of babies whose
`heads were 33 cm and not 32 cm as
`later recommended by the Ministry of
`Health in Brazil.
`Additionally, the state has not
`adopted either the RESP or the SINESC
`forms to report microcephaly and
`instead has created a third system for
`notifi cation. The numbers of notifi ed
`cases of microcephaly in different
`regions in Brazil, including the high
`number reported in Pernambuco,
`might therefore illustrate some of the
`disparities in the way microcephaly has
`been notifi ed since 2015.
`
`Underestimated?
`While some experts believe the
`number of potential Zika-related
`microcephaly cases is overestimated,
`others think it is underestimated
`because many pregnant women do not
`have any symptoms when infected by
`Zika. Thus, many cases of microcephaly
`are not reported in the RESP registry
`
`because no connection with Zika virus
`has been established.
`Additionally, Zika infection can only
`be confi rmed by PCR and the current
`capacity for doing PCR tests for Zika
`diagnosis in Brazil is very limited. Only
`five laboratories are equipped to do
`the test and together they run no more
`
`“...Health Minister Marcelo
`Castro and the Brazilian
`President Dilma Rousseff have
`both announced that the
`country is losing the battle
`against the mosquito.”
`
`than 100 tests per week. Even when PCR
`is available, the window of opportunity
`to do the test is very small as viral RNA is
`best identifi ed in the blood of infected
`patients in the first few days after
`symptoms appear.
`
`Reproductive issues
`Even though the alarming number
`of microcephaly notifications is still
`limited to Brazil, in some countries
`in
`the Americas—Colombia,
`Jamaica, El Salvador, and Panama—
`governments have advised women to
`postpone pregnancy. In Brazil, health
`authorities have not issued any offi cial
`statement in this regard, although
`Cláudio Maierovitch, the director of
`the communicable disease surveillance
`
`Christophe Simon
`
`524
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