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“Dengue in the time of Zika”
Meeting Report
2017 Americas Dengue Prevention Board Meeting
São Paolo, Brazil
3-4 August 2017
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AmDPB Meeting Report
In 2016, four leading organizations at the
forefront of dengue prevention and control—
the International Vaccine Institute, the
Partnership for Dengue Control Foundation,
the International Vaccine Access Center of
the Johns Hopkins School of Public Health,
and the Sabin Vaccine Institute—joined
forces to create the Global Dengue & Aedes-
Transmitted Diseases Consortium (GDAC).
The Consortium aims to promote the
development and implementation of
innovative and synergistic approaches to the
prevention and control of Aedes-transmitted
diseases, expanding each partner’s expertise
in dengue to the fight against diseases such
as Zika, chikungunya and yellow fever. Its
creation reflects the urgent need for global
coordination in the currently fragmented
efforts to control the diseases transmitted by
Aedes mosquitoes.
OBJECTIVES OF MEETING
The Americas Dengue Prevention Board held a meeting in São Paulo, Brazil on “dengue in the
time of Zika” organized by GDAC and co-hosted by the Brazilian Ministry of Health. The
objective was to define key issues and considerations in dengue prevention and control in the
context of the co-circulation of dengue and Zika, and to provide recommendations for needed
research and public health measures, especially for the Americas. Given this co-circulation and
the fact that the clinical manifestations of dengue and Zika are often similar, the meeting was
convened to address the potential complexities of epidemiology, surveillance, diagnostics,
disease pathology, vaccines and vector control.
CONTEXT
Today, the risk of epidemic arboviral diseases is at its highest in history. More than 3600 million
people live at risk of being bitten and infected through mosquitoes of the Aedes genus. Dengue
has been a major public health problem globally for decades, but the disease burden continues
to increase. Its geographic distribution is expanding (now affecting 128 countries, including
more than 40 countries in the Americas), along with increased epidemic activity,
hyperendemicity and emergence of severe disease. Recent outbreaks of yellow fever in Brazil,
Angola, the Democratic Republic of the Congo, and Nigeria underscore the very real threat of a
resurgence of this disease, with its high mortality and vaccine supply shortages. The list of other
arboviruses with the potential to emerge in urban populations through transmission by Aedes
mosquitoes is long, and includes other flaviviruses, bunyaviruses and alphaviruses. Of special
concern in the Americas are Mayaro fever and Venezuelan equine encephalitis viruses,
transmitted by Aedes aegypti and Aedes albopictus. Other routes of transmission of arboviruses
are being documented, such as through blood transfusion, organ transplantation, transplacental
route, sexual activity and possibly urine and saliva. We still have much to learn about the
biology and transmission dynamics of these viruses.
The emergence and spread of Zika virus constitute the latest challenge to global public health.
Zika is being driven by the same global trends (urbanization and globalization) that promote
dengue and chikungunya. In 2007, Zika virus
caused a small outbreak on Yap Island in
Micronesia and in 2013-2014 a larger
epidemic in French Polynesia. Those outbreaks
went relatively unnoticed until the virus
spread to the Americas where it caused
explosive epidemics in 2015-2016, associated
with severe neurological complications in
newborns. However, the burden of Zika and
the possible interactions with other
flaviviruses are not well understood.
There are several driving forces for the
dramatic geographic expansion of epidemic
arboviral diseases. Demographic changes
resulting from population growth have
resulted in uncontrolled urban development,
changing lifestyles, changes in agricultural
practices, land use and animal husbandry, and
deforestation. Factors favoring the spread of
arboviral diseases are prolific and growing,
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including the presence of tires, water containers and solid waste that is poorly disposed of.
Altogether, there is increased transmission and emergence of viruses with greater epidemic
potential. Effective vector control is lacking. Globalization with rapid intercontinental travel has
led to increased movement of people, animals (including vector mosquitoes), commodities and
pathogens and with urbanization poses major challenges to dengue prevention and control.
COUNTRY SITUATIONS
Updates from the health ministry representatives
Brazil
Over the past two decades, Aedes aegypti has spread throughout the country, with the
proportion of municipalities infested nearly tripling to 87% between 1995 and 2017.(see Figure
1) Aedes albopictus is also expanding its range, but to a lesser extent.
Figure 1 Distribution of Aedes aegypti in Brazil
Ministry of Health, Brazil, preliminary data- July (epidemiological week 28), Carvalho et al, 2014
Reporting of dengue, chikungunya and Zika is mandatory. In 2015-2016, 5·2 million cases of
suspected arboviral diseases in urban dwellers were reported (87% dengue and 7%
chikungunya), but the proportion of cases of Zika in that total is unclear. The transmission
season was longer than usual. So far, however, 2017 has had fewer cases of dengue,
chikungunya and Zika, in not only Brazil but Colombia also. The reason is not clear. Outbreaks of
yellow fever since 2015 have occurred mainly in areas of low vaccination coverage.1
Dengue. Between 1998 and 2013, five outbreaks of dengue were seen, due to all four serotypes
of dengue virus (DENV) in different combinations. Two major epidemics, predominantly due to
DENV-1, occurred in 2015 and 2016 (see Figure 2), with more than three million cases reported
and some 1700 deaths (mostly in over 30-year olds, with co-morbidities contributing to those
people aged over 60 years). Most deaths in the North region occurred in people under 50 years
of age, whereas in the South region, there were fewer deaths, mostly in people aged over 50
years. For the past five years the highest incidence rates have been seen in the Centre-West and
South-east regions, with lowest rates in the North and South regions. The State of Paraná, in the
South, introduced Sanofi Pasteur’s dengue vaccine, Dengvaxia® , in 2016 (see below).
Since 2013, there have been 8-10 week periods when more than 100,000 dengue cases per
week have been recorded, an unprecedented rate. In 2017, there have been no major outbreaks,
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but in line with epidemiological
forecasts some 207,000 cases were
reported by epidemiological week
30, with all four serotypes of DENV
circulating (50% of cases due to
DENV-4), with the North and
Centre-West regions mostly
affected. In 2015 and 2016, 3·17
million probable cases of dengue
were reported, of which 41,473
(2·5%) were in pregnant women.
The 2016 epidemic, with some 1·5
million cases, contained an
unknown number of cases of Zika,
and the disentanglement of the two
epidemics is a work in progress.
The epidemiological picture showed that the peak in cases of congenital Zika syndrome (CZS)
appeared in states, mainly in the north-east, that had not had recent large outbreaks of dengue.
Some have suggested that lower exposure to dengue in the past four years increased the
likelihood of CZS.
Challenges facing the country include the atypical 2017 season and the changing pattern of
serotypes. There is concern about the re-emergence of DENV-2, as is being seen in different
regions of the country, and higher rates of severe disease, hospitalization and death in under-15
year olds, as seen in 2008 in an outbreak in Rio de Janeiro. Viral serotypes, genotypes, subtypes
and clinical outcomes need to be monitored.
Zika. Zika virus was first detected in the country in 2015, in the state of Bahía (eastern Brazil). Clusters of an unknown exanthematic disease had been observed in several north-eastern states in July 2014, and in early 2015 people were presenting to health-care facilities in Pernambuco with itching and inability to sleep. However, some areas of Brazil have yet to experience an outbreak of Zika.
Subsequent genomic analyses of Zika viruses from people and mosquitoes analysed in mobile laboratories (a noteworthy innovation) as well as entomological and epidemiological data suggest that the virus was circulating unrecognized in north-eastern Brazil by late 2013 or early 2014.2 The viral genomic analyses also suggest that from Bahía it spread rapidly both to countries in the Caribbean, Central America and then Florida (USA),3 and throughout many parts of Brazil, where it caused two waves of outbreaks: September 2015 to April 2016 and May-November 2016.
During the 2016 outbreak, 17,000 cases were recorded in pregnant women (mostly detected in the second and third trimester), with a tail of 1900 cases in 2017 (see Figure 3). Among the cases reported in 2015-2016, a total of 1950 cases of Zika virus infection-related microcephaly in all regions were confirmed.4 (Other causes, such as syphilis, toxoplasmosis, other infections, rubella, cytomegalovirus infection and herpes simplex, were eliminated.) The first cases of microcephaly and then a marked increase in
Figure 2 Dengue probable cases, Brazil 2015-2017
Ministry of Health, Brazil, preliminary data –up to July 2017
(epidemiological week 28)
Figure 3 Zika probable cases Brazil, 2016-2017
Ministry of Health, Brazil, preliminary data – up to July 2017
(epidemiological week28)
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incidence were recorded in Pernambuco State in August 2016, while in the North, Centre-West, and South-east regions only small increases in the occurrence of microcephaly were observed. Some 76% of cases were recorded in the North-east region. Improved surveillance (both mandatory and sentinel) was introduced. In the second wave, Zika virus infection in pregnancy was well documented in all regions of Brazil, but no significant increase in confirmed Zika virus infection-related microcephaly was observed, except for a small rise in the Centre-West and the South-east regions. Most of the deaths were in the South-east. The 2017 data perhaps also represent the results of improved surveillance. Nevertheless, epidemiologists are expecting a much lower incidence of Zika virus disease in 2017.
In 2015, emergency meetings of the Brazilian public health authorities resulted in a declaration
of a public health emergency of national concern in November, followed by the WHO declaration
of a public health emergency of international concern in February, 2016, which was lifted in
November, 2016. Case definitions have been revised recently, with a more restrictive criterion
for head circumference. In early 2017, the health ministry issued revised and integrated
guidelines for surveillance and health care, including surveillance of malformations, monitoring
changes in growth and development in early childhood related to Zika virus infection (including
a reference measurement of head circumference) and neurological changes such as cranial
calcification, retinal lesions and changes in hearing at 1 month.5 As yet, however, there is no
national system for registration of birth defects, and a further problem is the lack of reliable
historical data on microcephaly. By epidemiological week 18 of 2017, the ministry had received
13,719 notifications since 2015 of microcephaly, of which 2772 were confirmed for Zika.
Congenital Zika syndrome is only one extreme of the spectrum of Zika virus disease, although
much remains to be learnt about the pathogenesis, including the fact that very little is known
about the effects of Zika virus infection in infancy.
Chikungunya. A different pattern to that for dengue has been observed. A small increase in the
number of cases at the end of 2015 prefaced a major outbreak in 2016 (more than 278,000
cases) and another in 2017 (157,000 cases up to epidemiological week 28), with 267 deaths.
The North-east region was particularly affected in 2016-2017 (with incidence rates of
355/100,000 and 170/100,000 population, respectively, for each year) followed by the North in
2017 (incidence rate 66/100,000 population in 2017).6
Colombia
The country has a systematic mechanism for surveillance (Sivigila), including geographic
information systems for mapping.7 It covers nearly 1000 municipalities, about 80% of which are
at risk of arboviral infections, and of which many are hyperendemic for dengue.
Figure 4 Reported cases of dengue, chikungunya, and Zika, Colombia, 2008-2017
Sivigila, Instituto Nacional de Salud, Colombia, 2016
0
5000
10000
15000
20000
011121314151081828384806162636460414243444021222324252102030405008182838480515253545031323334301
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
No
tifi
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ases
Epidemiological year and month
dengue chikunguña zika
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The country has also experienced outbreaks of other vector-borne diseases, including Zika, and
faces the threat of unrecognized emergent viruses. Outbreaks of chikungunya were seen in 2015
and 2016, and of Zika in 2016, both coincident with peaks in dengue incidence (see Figure 4).
Zika. The first cases of Zika virus infection were detected in September 2015, and by December
2015, national tracking programs had been set up to monitor pregnant women for signs of
infection and to spot early signs of birth defects in fetuses. A national network of researchers
and public-health institutions was also established. Nearly 107,000 clinically suspected cases of
Zika were reported in 2016 (including reports from 800 municipalities), but confirmation can
only be done by the national reference laboratory. Cases continue to be reported in 2017 but in
smaller numbers. The entry point for the virus appears to be from the Caribbean. In 2016, the
National Institute of Health reported cumulative totals of 19,746 pregnant women infected with
Zika virus, 180 infants with microcephaly (with 100 more probable cases under investigation)
and 692 cases of neurological complications associated with the virus. Cases continue to be
recorded in 2017 (see Figure 5). Differences between territories and facilities hinder analyses.
Figure 5 Incidence of the congenital syndrome associated with Zika virus, until 17 February 2017
Sivigila, Instituto Nacional de Salud, Colombia, 2016 - 2017
Dengue. Many cases of dengue have been reported with several epidemics in 2013-2017,
although the high numbers recently may reflect better surveillance. All four serotypes have been circulating since 2011, with DENV-2 predominating in 2015 and 2016. Data for 2017
(17,243 cases by epidemiological week 30, of which 40% had signals of alarm and 1% were
severe) show that most severe disease is being seen in the 1-4 year and over-65-year age
groups.
Sentinel surveillance for other arboviruses has been implemented, but so far no yellow fever has
been seen. Concerns raised include the need to sustain high-quality surveillance, especially on
symptomatic Zika virus disease and Guillain-Barré syndrome (GBS). Further vigilance is needed,
for instance in border regions as the epidemiological situation in neighbouring Venezuela is not
known. Also, further work is needed to clarify the natural history of Zika and chikungunya
infections.
Mexico
The National Epidemiological Surveillance System (SINAVE) operates a robust system of real-
time monitoring of dengue, Zika and chikungunya, linking surveillance and laboratory results,
and publishes data weekly. It operates from the federal to the local level, and includes a wide
network of laboratories (as part of the country’s response to the requirements of the
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International Health Regulations (2005)). A triplex assay is used to detect dengue, Zika and
chikungunya viruses (an outbreak of the latter in 2015 resulted in nearly 13,000 cases8) (see
Figure 6).
Figure 6 Confirmed cases of dengue, chikungunya, and Zika by week, Mexico, 2015-2016
SINAVE/DGE/SS. Sistema de Vigilancia Epidemiológica de Dengue/ CHIK/Zika. * Hasta el 17 de julio de 2017
Dengue. Since 2000, dengue has appeared cyclically, with epidemic peaks in 2007, 2009, 2012
and 2013 and incidence rates reaching 54/100,000 inhabitants in 2013 (64,000 cases). All four
serotypes have been circulating together, but in the past decade, DENV-1 and DENV-2 have
dominated; this contrasts with the dominance of DENV-3 two decades ago. In 2017, the
distribution of serotypes varied widely across the country, with the highest incidence
(10·4/100,000 inhabitants due to serotypes 2, 3 and 4) in Chiapas in the south and rates half as
high and due to various combinations of serotypes 1, 2 and 3 in other southern and eastern
parts of the country.
Zika. The first autochthonous cases, identified in November 2015, were associated with South America, with links to Colombia. In 2016, a major outbreak occurred with 8554 confirmed cases, followed by a marked decline in numbers in 2017.
Health ministry guidelines specify testing of all pregnant women for Zika virus infection and, in areas where there is no documented transmission, testing of 5% of the rest of the population. In 2016, 5065 cases were confirmed in pregnant women, with 278 so far in 2017. Most infections occurred in the second and third trimesters. Six cases of congenital Zika syndrome and 15 of GBS have been confirmed according to strict protocols. The 2016 guidelines for epidemiological monitoring and laboratory diagnosis of infection with Zika virus in Mexico propose that 10% of patients with confirmed Zika virus infection be tested also for dengue and chikungunya to identify possible co-infections.
The health authorities are prepared for possible continued transmission of Zika virus, in particular, in areas where it has not previously been found, and for possible cases of congenital Zika syndrome and GBS. They are also preparing for the reappearance of yellow fever and Mayaro fever virus through entomological monitoring. The arrival of Zika virus led to a revision of the surveillance strategy with inclusion of multiplex PCR and serological testing, the development of a diagnostic algorithm, and strengthened epidemiological and laboratory surveillance with geolocation capabilities.
Overall. For the three countries, few cases of concurrent dual or multiple infection have been reported, although data are limited – one reason may be a bottleneck in laboratory testing and limited availability of tests. Shared issues of concern include the changing pattern of DENV
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serotypes, possible interactions between past and present flavivirus infections, the different but overlapping symptomatology of dengue, chikungunya and Zika disease, and the uncertainty and variability of assumptions made in mathematical modeling which render difficult the forecasting of outcomes of outbreaks and the impact of introduction of vaccines and vector control methods.
The epidemiological outcome of Zika virus depends on local ecology, the natural history of the
viral infection, the population’s susceptibility to infection, and possibly the strain of virus. After
the initial post-invasion epidemic, Zika virus may either become extinct locally or be maintained
through endemic human spread or sylvatic transmission. It is possible that variations in
temperature and rainfall associated with recent La Niña and El Niño events may have affected
transmission of all three viruses throughout the Latin American region.9
CLINICAL ASPECTS AND DIFFERENTIAL DIAGNOSIS
The potential cross-reactivity among co-circulating flaviviruses has complicated serological
approaches to differentially detecting Zika and dengue virus infections, accentuating the urgent
need for specific and sensitive tests. In patients with febrile illness, the diagnosis of dengue,
chikungunya and Zika is mainly clinical.10 Differential diagnoses are necessary not only for
clinical management, but also to improve the surveillance system, for early detection of
outbreaks, and to evaluate the efficacy and the impact of interventions.
Many studies have looked at how to diagnose dengue. Rapid tests for NS1 DENV antigens have
good specificity but sensitivity needs to be improved; furthermore, they are not widely available
or easy to use. Traditional means have relied on an algorithm that uses patient age, white blood
cell count and platelet count to discriminate dengue cases from non-dengue cases, but recent
work supports the value of using lowered leukocyte counts and raised transaminase activities
for differentiating dengue from other febrile illnesses in children.11 Additionally, several signs
and symptoms, including vomiting, as well as higher viremia and positivity in the NS1 antigen
rapid test may be predictors of severe dengue.12
The rate of Zika virus infections that leads to symptomatic disease is variable, with symptoms
beginning on average 6 days (range 3-11 days) after infection and persisting for 1-2 weeks.
Symptoms are mostly mild and typically non-specific, including maculopapular rash,
conjunctivitis, fever, headache, and joint and muscle pain. The cranial morphology and brain
findings have been described elsewhere. The incidence of GBS after infection is about
0·24/1000 Zika virus infections. IgM antibodies appear on average 9 (range 4-114) days after
infection, followed by IgG antibodies at 10 (2-19) days.
A Brazilian study looked at Zika infections during simultaneous epidemics of dengue and
chikungunya, finding that the presence of rash with pruritus or conjunctival hyperemia, without
any other general clinical manifestations such as fever, petechiae or anorexia, is the best Zika
case definition.13 A large, passive, facility-based study in Colombia compared signs and
symptoms in patients with dengue (serotypes 1, 2 and 3), chikungunya and Zika, indicating that
warning signs for severe dengue may allow differentiation from chikungunya and Zika disease.
Other studies have reported high fever and arthritis as more common with chikungunya, and
rash followed by body aches with low fever with Zika. Zika patients were characterized by lower
odds ratios compared with dengue and chikungunya patients for fever, fatigue, headache, retro-
orbital and neck pain, nausea/vomiting and diarrhea (the last two signs being useful where
there were no laboratory facilities). Clinical algorithms will likely be required to guide the use of
sensitive and specific diagnostic tests for dengue, and warning signs for severe dengue may
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allow differentiation from chikungunya and Zika. The availability and use of simple laboratory
tests would aid diagnosis of dengue.
DIAGNOSTIC TESTS
The spread of Zika virus has complicated existing serological tests for dengue. Therefore, the
“gold standard” for diagnosing flavivirus infections is currently either virus isolation or
detection of viral RNA by RT-PCR. These are hampered by low sensitivity and the short duration
of viremia. Available serological tests include measuring neutralizing antibody titers by plaque-
reduction neutralization tests (PRNT) and IgM-capture assays (ELISA), which are highly
influenced by cross-reactive antibodies and have low specificity.
A US-Brazilian research project set out to detect recent exposures to both dengue and Zika
viruses, using an ELISA with specific IgG3 antibodies.* The assays confirmed recent infections
with dengue or Zika virus within 30 days of onset of symptoms, showed high specificity, gave
reproducible results and are simple and affordable. High anti-IgG titers against NS1 and
envelope antigens of DENV were found to reduce the probability of seroconversion in Zika virus
infection. After successful validation, the National Institutes of Health in the USA have submitted
an application to the US Food and Drug Administration for an Emergency Use Assessment and
Listing. The assay has been shared with several other academic laboratories and will be
supplied for use in the multi-country study of Zika in infants and pregnancy sponsored by the
US National Institutes of Health and Fundação Oswaldo Cruz (Fiocruz).
In another approach, an international collaborative project has developed a NS1 blockade-of-
binding ELISA that distinguishes between dengue and Zika virus antibodies.14 It uses specific
monoclonal antibodies derived from subjects infected with DENV or Zika virus, in particular one
Zika monoclonal antibody for a binding site on the NS1 protein that was not competed for by
cross-reactive antibodies. It was field tested in laboratories in five countries, including
Nicaragua and Brazil during the Zika epidemic, using a large number of well-characterized
samples from confirmed Zika virus infections, primary and secondary DENV infections,
individuals with other flavivirus and other virus infections or vaccinations, and healthy control
patients. The assay was found to be robust, highly sensitive and specific, and low cost. This
assay could be applied to Zika surveillance, seroprevalence studies, and intervention trials,
while the IgG3 assay can determine recent exposure.
FLAVIVIRUS IMMUNITY
Some flaviviruses, including Japanese encephalitis, tick-borne encephalitis and yellow fever
viruses, are neurotropic, have a single serotype, and induce homotypic immunity. Dengue is
different in having increased risk from sequential infection by different serotypes. Zika virus is
virologically similar to non-dengue flaviviruses, but, like DENV, can manifest infrequent, severe
clinical phenotypes.
Antibody-dependent enhancement (ADE) is an immunopathologic phenomenon which explains
why sequential heterotypic dengue virus infection is associated with an increased risk of a
severe dengue clinical phenotype. With DENV, ADE is primarily an in Vitro phenomenon, but it
has been documented in vivo small animal models and cohort studies for human infections
* IgG3 antibodies have a half-life of only about 7 days compared with about 3 weeks for the other three classes
of IgG antibodies and are strong complement activators.
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AmDPB Meeting Report
(associating neutralizing antibody titers collected before infection with clinical outcomes
following infection). But the data are variable, and there are contradictory data and
methodologic questions which challenge the ADE hypothesis.
Recent research has looked at the behavior of Zika virus and antibodies in cell lines, animals and
humans, revealing a complicated picture. Some in vitro studies have shown that human
antibody responses after DENV infection are highly cross-reactive to Zika virus. Dengue-derived
monoclonal antibodies (mostly to DENV envelope protein) enhanced Zika virus infection of Fcγ
receptor-bearing cells; antibodies to linear epitopes bound, but did not neutralize, Zika virus
and promoted antibody-dependent enhancement, implying modulation of virulence and disease
severity. Monoclonal antibodies against envelope domain I/II of Zika virus potently enhanced
both Zika and DENV infection in vitro and lethally enhanced DENV infection in mice. In contrast,
monoclonal antibodies against envelope domain III were specific and neutralizing, sufficiently
to warrant consideration of the epitope as a candidate for a Zika vaccine.
However, studies in larger animals have not shown that pre-existing dengue immunity resulted
in more severe Zika virus disease and may actually shorten the duration of Zika viremia. These
studies also showed that pre-existing immunity to antigenically-related flaviviruses neither
diminished nor increased Zika virus titres and did not change the kinetics of the immune
response. Further, the viral load of Zika virus was the same in Zika-infected patients who had
been previously exposed to DENV as in those who had not. Follow-up of women infected with
Zika virus in pregnancy showed no association between disease severity and abnormal
outcomes or viral load, adverse outcomes and viral load, or presence of pre-existing dengue
antibodies with degree of severity, viral load or adverse outcome. These epidemiological data
from Brazil are suggestive of previous dengue infection providing some cross-protection against
ZIKV.
Great caution needs to be applied to interpreting the results of in vitro, in vivo animal
experiments, and epidemiological observations for human infections and immunopathological
responses. Prospective and retrospective epidemiological studies together with determination
of the specific target sites of Zika virus infection in humans are needed in order to assign
association or causality.15
VACCINES AND PREPARATION FOR VACCINATION PROGRAMMES
To prepare for the possible introduction of Dengvaxia® into the Brazilian National
Immunization Programme, morbidity and mortality data on some 10 million cases of dengue
were reviewed. Although only about 30% of cases were laboratory confirmed, a trend was
noticed towards more cases in younger people. The average delay in seeking health care was
three days after symptoms appeared (range 1-24 days). Most admissions to hospital were due
to infections in particular with DENV-2 and to a lesser extent DENV-3; other risk factors for
admission were age (after a peak at 6-10 years of age, admissions increased with the age over
50 years), living in the north-east and delay in seeking care. Generally, the proportion of cases
admitted to hospital has fallen over the years. Mortality was associated with age, infection with
serotypes 2 and 3, pregnancy (the risk was three times higher in pregnant women) and
infection in third trimester, and lower educational levels.
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Considerable changes were observed in
circulating serotypes and numbers of cases,
both temporal and geographically (see Table
1), even down to municipality level - this
clustering of infections makes forecasting
and projections difficult. Wide gaps were
observed between the North/North-east and
South regions. However, reported
seroprevalence rates of dengue often
underestimate the actual rates, and analyses
of age-related data illustrate this (with high
kappa parameter values), possibly owing to
the arrival of Zika virus. Modeling can
provide projections that reflect
epidemiological patterns observed. Other
models can look at the potential impact of vaccination and different control methods.
Paraná State
In 2016 the Government of Paraná State in Brazil became the
first authority in the Americas to introduce public vaccination
with Dengvaxia® . It was the first such campaign for a state
public system in Brazil. The decision to use the vaccine was
reached based on a strategy to control dengue using a new tool
and epidemiological criteria. Challenges included the fact that
it is difficult to introduce a new vaccine; the age groups
targeted were not accustomed to attend health services and
undergo vaccination; relatively fewer cases of dengue were
seen in the State compared to some other states during the
months of vaccination; and the whole program would cost
US$ 30 million which is about 2.6% of the budget of the State
Secretariat of Health.
The State authorities justified the dengue vaccination
programme as a response to a three-fold increase in incidence
of dengue since 2013, culminating in its worst epidemic in
2016 when all four DENV serotypes were present. Some nine
million people (more than 80% of the State’s population) live
in areas where dengue virus is circulating and there is a high
infestation rate of Aedes aegypti.
The criteria for selecting municipalities as vaccination sites
were that they should have experienced three or more
outbreaks in the past five years and an incidence rate in 2015-
2016 of >500 cases/100,000 inhabitants (28 centers), or that
there had been more than 8000 cases/100,000 inhabitants in
2015-2016 (2 centers). People aged 9 to 44 years were
vaccinated in the latter and those aged 15 to 27 years in the
former. In preparation, health care and other professionals
were informed and trained, vaccination protocols developed,
Table 1 Dengue and Zika Cases by Region, Brazil, 2016-2017
Created by Dr. João Bosco Siqueira Jr.
Figure 7 Advertising campaign second
stage- March 2017
http://www.saude.pr.gov.br
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AmDPB Meeting Report
partners in the private and public sectors mobilized, media campaigns undertaken to raise
public awareness, and an electronic State registry system established. A three-phase
programme is being implemented.
In the first phase, in August-September 2016, more than 200,000 people were vaccinated, with
coverage rates of 50-80% achieved in 17 municipalities. In the second phase (over five weeks in
March-April 2017), vaccinations were administered in both health units and mobile units, with
a first dose offered to those missed in the first phase. Appeals for uptake of the second dose
were made by direct mail and social media to those already vaccinated. The programme was
supported by media campaigns, including radio, television and social networks. Coverage rates
rose to 80-100% in 19 municipalities, with only one of the rest below 50%. The third phase in
September 2017 will see third and second doses administered to the previously vaccinated
cohorts. So far, 453,000 doses of vaccine have been administered. Altogether 660 adverse
events have been recorded, most of them reporting symptoms in the local injection (red skin,
edema, discomfort) and four cases requiring hospitalization (not related to vaccination).
Studies are planned to evaluate effectiveness of the vaccine and to continue to monitor for
adverse events. The State’s health surveillance programme has earmarked funds for monitoring
arboviral diseases and vector control. An intersectoral committee meets monthly to review
progress against dengue.
Financing strategies
Financing remains one of the main hurdles to new vaccine introduction and delivery at the
national level. The cost of immunization programs is rising because of higher prices of new and
underused vaccines, the need to expand vaccine supply chains, additional costs of training staff,
and conducting expanded surveillance and monitoring activities. The main considerations for
successfully financing the introduction of a dengue (or Zika) vaccine in the Americas are:
affordable pricing (and, concurrently, experience with pricing negotiations), the ability to
include new vaccines in the
vaccine budget, the
availability of sufficient fiscal
resources, sustainability of
funding, and the capacity to
take on new funding.
In many countries in Latin
America, general taxation is
the primary source of
funding public health care –
a traditional means of
financing along with social
health insurance. Alternative
or additional sources of
funding capable of generating more than US$ 100 million (see Table 2) include pooled
procurement, and regional and domestic taxes.16 Low-interest multilateral loans and debt buy-
downs or concessional loans have the potential to raise up to US$ 100 million a year. All have
different pros and cons. PAHO’s Revolving Fund is a successful mechanism for the joint
procurement of vaccines (see Figure 8) and has played a pivotal role in providing countries of
Table 2 Financing options for the Latin America and the Caribbean region
Constenla and Clark, 2015
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the Latin America and the Caribbean region with access to vaccines, syringes and other related
medical supplies at affordable prices. Rather than raising funds it allows existing money to go
further. The global air ticket levy raises some US$ 200 million for UNITAID; the Latin American
region could establish an equivalent specifically to support health or vaccination goals or try to
persuade UNITAID to extend its remit to dengue, Zika and other vaccines. Several examples in
the region illustrate how specific domestic taxes can generate funds for broad health
programmes (as with VAT schemes in Bolivia, Chile and Ecuador and earmarked taxes on
alcohol and tobacco in Costa Rico, Ecuador and Panama). Although the World Bank and the
Inter-American Development Bank already provide low-interest multilateral loans, they have
not been specifically to support vaccine purchase and introduction.
Countries need to take several steps to prepare the ground for successful and sustainable
funding. These include: determining the price of the vaccine and ensuring the availability of
appropriate expertise in price negotiations; assessing their sources of funding and identifying
complementary funding mechanisms; considering procurement mechanisms; creating a budget
line item for implementation and delivery of a dengue and Zika vaccine program and
performing a fiscal space analysis in terms of the immunization budget, monitoring and
evaluation, and maintaining financing for existing vector-control strategies. In addition, they
should estimate overall program costs, undertake budget impact analysis to identify the impact
of a new vaccine on national health budgets, propose means of evaluation, and expand legal
frameworks to ensure sustainable financing of immunization programs.
ISSUES CONDUCTING TRIALS OF DENGUE VACCINE CANDIDATES WITH ZIKA VIRUS CO-
CIRCULATION
Sanofi Pasteur began its five-year Phase III trial (CYD15) of CYD-TDV (licensed as Dengvaxia) in
five countries or territories† in the Americas in 2012, recruiting 20,869 subjects aged 9-16 years.
A challenge came in March 2016 with outbreaks in all the trial sites of Zika virus leading to an
amendment to the trial’s protocol: blood samples from subjects with febrile illness would be
tested for Zika as well as dengue virus retrospectively and prospectively. Samples collected at
defined endpoints would be tested for neutralizing antibodies to Zika virus and samples from
febrile subjects would be tested by RT-PCR for a differential diagnosis. New observational
objectives are being added to the protocol, including the clinical manifestations of Zika virus
disease and antibody responses to dengue and Zika viruses, with new endpoints, including
† Brazil, Colombia, Honduras, Mexico and Puerto Rico (USA).
Figure 8 PAHO Revolving Fund
Courtesy of Jon Andrus
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detection of Zika virus infection in acute samples, genomic sequencing of Zika viruses in acute
sera, and measurement of neutralizing antibodies against dengue and Zika viruses. Further
studies will be undertaken in Latin America: to assess the case definition of Zika virus disease,
including surveillance of potential markers of probable clinical disease and the sensitivity and
specificity of molecular tests on blood and urine; to describe seroprevalence rates of both
dengue and Zika at baseline and one year after enrolment; and to develop the operational
infrastructure for potential Phase III Zika trial sites.
A microneutralization assay for Zika virus infection has been developed because of the high
demand for testing: by the end of the trial in June 2018 some 13,600-18,400 samples are
expected to be available for testing. PCR testing has been sourced to a national reference
laboratory in the USA. Zika virus will be sequenced by the US National Institutes of Health and
the results will be posted on publicly available databases.
In October 2015, the national ethics council in Brazil gave its approval for Phase III trials of the
live attenuated tetravalent dengue vaccine TV003 (Butantan-DV), being developed by
Instituto Butantan in Brazil and the US National Institutes of Health. The study was launched in
early 2016, with one study clinic opening in February 2016. The trial protocol was amended to
verify potential interactions between vaccination against dengue and exposure to arboviruses
(specifically Zika and chikungunya), considering that this exposure might occur before or after
vaccination; the amendment was approved in July 2016. Additional trial sites opened, and active
surveillance for the three viruses was initiated. Laboratory confirmation of infections was done
with a NS1 rapid ELISA and RT-PCR for all three viruses. The year 2016 saw the incidence of
Zika infection decreasing but not disappearing while an outbreak of chikungunya persisted until
late in the season and continued, at lower levels, in 2017. At the same time, cases of yellow fever
were reported in the 2016-2017, mostly in the east of Brazil, raising concerns.
Takeda’s live attenuated tetravalent dengue vaccine, TDV, is also in Phase III trials, with so
far more than 17,000 participants (including 15,000 children) having received at least one dose
in Phase I, II and III studies so far. Two studies have recently been initiated: DEN-313, looking at
cell-mediated immunity in 200 children in Panama and the Philippines, and the Phase III pivotal
efficacy trial, DEN-301, which has recruited 20,100 subjects aged 4-16 years in 26 sites in 8
countries including locations in Brazil, Colombia, Dominican Republic, Nicaragua and Panama
with diverse exposures to Zika virus and other flaviviruses (including JE and YF vaccination).
The DEN-301 study has been carefully designed, to determine vaccine efficacy against dengue of
any severity in all subjects including by baseline dengue serostatus and by dengue virus
serotype, with at least weekly active febrile surveillance throughout 57 months for each subject.
Baseline serum samples have been collected from all subjects, and acute and convalescent
serum samples are being drawn from subjects with febrile episodes. These samples will allow
additional analysis in the event of any strong vaccine-effect signals not related to serotype
circulation or dengue serostatus. First results are expected in late 2018.
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Dengue and Zika vaccines
An update was provided on the status of clinical
trials and development of several candidate dengue
and Zika vaccines. WHO has created a web site that
records publicly available information on vaccine
trials, including dengue and Zika vaccines (see
Figure 9).17 For dengue, besides the one licensed
vaccine and the two in Phase III trials (see above),
four more are in Phase I or II trials (see Table 3) and
at least another 16 candidates are in preclinical
development.18 In its position paper on Dengvaxia® ,
WHO recommended that countries should consider
its introduction in geographic settings (national or
subnational) of high endemicity (about or greater
than 70%), but not where the seroprevalence of
dengue was less than 50% in the age group targeted
for vaccination.19 WHO has issued tools to support
country’s decision-making processes, including a
guide on serosurveys, a global dengue transmission
map and principles and considerations for adding a
new vaccine to a public immunization programme.20
Several lessons have been learnt from work on first-generation dengue vaccines. These include:
early clinical studies are valuable to determine infectivity of live attenuated vaccine viruses,
including type-specific immunity; neutralization tests are still the best assay of immunogenicity for dengue vaccines, but do not distinguish between type-specific and cross-neutralizing
antibodies; controlled human infection model Phase I trials can provide initial proof-of-concept
that a vaccine has clinical benefit; baseline dengue serostatus needs to be determined for the
entire vaccine cohort, and safety and efficacy by serostatus should be presented in a stratified
Figure 9 WHO Vaccine Pipeline Tracker
http://www.who.int/immunization/research/vaccin
e_pipeline_tracker_spreadsheet/en/ Table 3 Overview of dengue vaccine characteristics
Modified from Vannice KS et al., Vaccine 34 (2016) 2934-2938
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AmDPB Meeting Report
analysis; immunogenicity and efficacy results should be interpreted in the context of potential
transient heterotypic immunity that could wane over time, indicating the need for prolonged
active surveillance; and, for licensure, vaccine efficacy should be demonstrated on the basis of
clinical endpoints. The effect of co-circulating flaviviruses, in particular Zika virus, requires
close scrutiny (see below).
WHO and UNICEF have defined
a Zika vaccine target product
profile on the basis of the public
health objective of prevention
of congenital Zika syndrome in
emergency or outbreak contexts
through the protection of
pregnant women with as a
priority vaccination of women
of reproductive age.21 So far, 45
candidates are known to be in
development: 18 subunit and
27 whole virus (see Figure 10) -
a broad and diverse pipeline.
Two (nucleic acid-based candidates) are in Phase II or I/II trials and five (with DNA, inactivated
virus, peptide or live attenuated virus platforms) are in Phase I trials. The prospects are
encouraging. Animal tests show protective efficacy of some candidates. Acute infection is
cleared by the immune system and neutralizing antibodies can be protective.
Evaluation of Zika virus vaccines, however, faces numerous challenges, covering clinical
evaluation and outcomes, safety, epidemiology, and public health need. Several questions
remain, including the effects of pre-existing flavivirus immunity and co-circulating flaviviruses,
together with gaps in our knowledge, such as the full spectrum of Zika illness, the burden of
disease, how the epidemiology will evolve, and what will be the need and best strategy for a
Zika vaccine? Experience with rubella vaccine in eliminating rubella could serve as an example.
VECTOR CONTROL
Using Wolbachia for biological control
The World Mosquito Program, an international collaborative effort, is using infection of
mosquitoes with Wolbachia, a naturally occurring bacterium, to reduce the ability of Aedes
aegypti mosquitoes to transmit dengue, yellow fever, chikungunya and Zika viruses to humans.
The bacterial infection diminishes the potential of mosquitoes to transmit chikungunya virus,
reduces the presence of detectable DENV (all four serotypes) in mosquito saliva by 70-80% and
completely blocks transmission of Zika virus. Recent reports further indicate that infection of
mosquitoes with Wolbachia may reduce the transmission of chikungunya22 and yellow fever23
viruses to humans. The Wolbachia-infected mosquito populations can spread and become self-
sustaining.
The method is simple and affordable, does not need the release of large numbers of mosquitoes,
has no reported adverse effects (from field trials in 160 sites including some in Brazil and
Colombia), and may have a considerable impact on disease transmission. Ethical and regulatory
approvals were obtained before project activities.
Figure 10 WHO Vaccine Pipeline Tracker: Zika vaccine candidates
Slide adapted from courtesy of D. Kaslow
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In Rio de Janeiro (Brazil), a Wolbachia project initiated in 2012 was initially designed to counter
dengue, but has now been expanded, with approval, to cover chikungunya and Zika. It began
with collection of mosquitoes in order to determine the number of infected mosquitoes to
release. A major exercise was undertaken to win community support, with mapping of
stakeholders, awareness campaigns, public surveys, mass media campaigns and events (for
example in schools). Once community engagement had been secured, in 2015-2016 Wolbachia-
infected mosquitoes were reared, released and trapped to assess the spread of Wolbachia (so as
to ascertain when to stop releases). (Fiocruz is expanding its mosquito-breeding capacity to a
capacity of 3·5 million pupae a week.) Nearly all mosquitoes in the field were found to be
infected after about 18 months, and the bacteria were considered to be self-sustaining in the
local mosquito population. In 2017-2018, a significant expansion is planned, aiming to cover
three million people in three cities (Niterói, Rio de Janeiro and Belo Horizonte). Epidemiological
studies will be conducted to measure the impact.
In Colombia, pilot projects in Medellín (with 145 release sites for a population of about 2 million)
and París (Bello, in Antioquia) are being expanded. Modeling studies for the two sites predict
that the project may reduce incidence of dengue and Zika by more than 90% for at least 20
years. In 2017, the Eliminate Dengue Program is extending its five original pilot schemes to 12
countries, including Mexico (for which plans are well advanced) and later Argentina and
Panama. The Program will help design the projects and provide training, technology and
support such as data management at no cost. It is seeking partnerships with public health
agencies for further expansion.
At its meeting on mosquito (vector) control emergency response and preparedness for Zika
virus in March 2016, WHO’s Vector Control Advisory Group recommended the carefully planned
pilot deployment of Wolbachia in operational conditions accompanied by rigorous independent
monitoring and evaluation that builds entomological capacity to support operational use. It also
recommended continued planning for randomised control trials with epidemiological outcomes
in order to build evidence for the routine programmatic use of Wolbachia against Aedes-borne
diseases.
Integrated vector control and vaccine strategies
Countries in the Americas have been leaders in eradicating Aedes aegypti and reducing disease
incidence (in particular yellow fever), with notable successes recorded over the past century. In
some instances, the reasons for success were a condition of the times, including autocratic but
supportive governments and top-down paramilitary programs, along with detailed mapping
and control of larval habitats, dedicated and well-trained staff, smaller cities, fewer tires,
plastics and disposable containers, minimal air travel, adequate funding, regional programs and
widespread use of an effective insecticide (DDT). Subsequent failures of control programs have
been associated with global and national policy changes in the 1970s, the adoption of space
spraying against Aedes aegypti mosquitoes, the general deterioration of public health
infrastructure in some situations, and coincident economic and global trends such as population
growth, urbanization and globalization. Underlying these failures were factors such as
complacency and apathy, lack of political will and economic support, reactive control responses
(too little, too late), a lack of community ownership and partnership as well as a host of
weaknesses in Aedes control operations including a lack of trained personnel. The result is that
traditional vector control methods have generally been unsuccessful; in particular, vector
control has failed to prevent epidemics of dengue, chikungunya and Zika.
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Current and future prevention and control measures for dengue include vaccines, antiviral
medicines, therapeutic antibodies, and mosquito control, ideally utilized through an integrated
approach (see Figure 11). Promising new vector control tools include lethal ovitraps, spatial
repellents, new residual insecticides, insecticide-treated curtains and screens, harborage
spraying (against Aedes albopictus), sterile male mosquito releases, entomopathogenic fungi,
and infection of mosquitoes with the bacterium Wolbachia. None of these methods is likely to
succeed if used alone, and will need proper implementation by trained personnel and
surveillance for resistance. Although vaccines will likely be implemented concurrently with
vector control, epidemiological trials are needed to quantify the protective effectiveness of
vector control interventions alone and in combination, and to provide baseline data. One four-
armed trial could compare the impact of vaccination, vector control, and the two combined
against no intervention.24
Many new approaches will face challenges of implementation in massive urban areas and will
need extensive community engagement programs and public education. Their success will also
need the involvement of policy-makers and legislators, communication between technologists
and politicians, and intersectoral cooperation.
WORKING GROUPS
In three working groups, the participants considered the ways forward in terms of surveillance
and epidemiology, diagnostics, and prevention and control of dengue. The first group, on
surveillance and epidemiology, confirmed the need for better evaluation of severe cases and
better understanding of the interaction between dengue, Zika, chikungunya, and other arboviral
diseases, especially in the context of changes in DENV serotypes. The latter needs timely
reporting, better training of clinicians and health care staff on the evaluation of patients
presenting with clinical symptoms that are consistent with dengue, Zika or chikungunya, and
greater clinical proficiency in diagnosis and management. Countries should take up PAHO’s
work on developing key laboratories to extend the diagnostic network and on its Integrated
Arbovirus Management Strategy.
Enhanced surveillance of severe arboviral disease and neurological complications, in particular
severe dengue, congenital Zika syndrome and GBS, was also vital, and should be accompanied
Figure 11 GDAC Paradigm to Rollback Dengue and other Aedes-transmitted
diseases using new tools in the control pipeline
Created by Prof. Duane Gubler
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by follow-up in order to understand the clinical course of these conditions, develop case
definitions and design algorithms for assessment and classification. Countries should introduce
simultaneous RT-PCR testing for dengue, Zika and chikungunya infections and be supported in
so doing. Surveillance should be harmonized between countries in the region, with steps taken
to ensure intercommunicability of electronic data systems. PAHO’s Health Information Platform
for the Americas (PLISA) offered a valuable means of sharing information.
For congenital Zika syndrome and follow-up of the affected pediatric population the group
urged integrated approaches to research into the full spectrum of the adverse effects of Zika
virus infection, surveillance and clinical management (as with the protocol used in Brazil), and
enhancing the capacity and capabilities of health professionals.
The second group, on diagnostics, recognized that, even though acute care should be based
mainly on clinical judgment, laboratory assays had a clinical role besides their essential function
in surveillance, epidemiological studies and clinical trials. They contributed to informing public
health interventions. It also recognized the complications arising from co-circulation of viruses
and vaccination.
Diagnostic assays had some weaknesses. PCR was not available everywhere and laboratory
proficiency was variable. Sensitivity depended on the pathogen, type of sample and timing of
collection. Cross-reactivity was a problem for antigen-based NS1 assays, IgM and IgG ELISAs,
and neutralization assays (which are resource intensive and impracticable for most
laboratories).
Remaining problems to be resolved included cross-reactivity. Needs identified included: the development and availability of point-of-care assays to accurately differentiate co-circulating flaviviruses; development of diagnostic algorithms that included more accurate and simple-to-use tests as well as those designed for negative samples; serological assays with higher throughput; greater availability of reagent validation panels; and the expansion of laboratory networks, including national and international reference laboratory capacity, and better communication between them, and the capability to respond to new emerging or re-emerging viruses. The third group, on prevention and control, considered several aspects. For vector control, it recommended the re-evaluation of current strategies with estimates of associated societal and/or governmental costs; the creation of protocols for complementary assessment of new and existing technologies and evaluation of cost-effective strategies across different countries; evidence-based applications following pilot studies and greater adherence to WHO’s guidelines; commitment of health ministries to establish long-term sustainable programs; and measurable outcomes in strategies.
Funding remains a major consideration and funding bodies should be identified and listed. Countries’ funding structures should be determined, with clear identification of full spending and allocation of resources. The regulatory landscape for all vector control and vaccination strategies should be mapped by country and region with shared pathways identified. Companies and academic institutions should be encouraged to fund studies that look at the impact of vector control strategies and vaccination programs. Technical cooperation between countries should be encouraged to increase quality and representability of the studies.
More and better data are needed from health ministries and other governmental bodies in order to calculate estimates of disease burden and to provide baselines for modelling efforts and clinical trials.
Preparation and planning needed greater emphasis. Highlighted strategies and activities included the creation of a road map for introduction of both vaccination and vector control
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AmDPB Meeting Report
programmes, alone or in combination; identification of research gaps and missing data, such as those on efficacy; continued re-assessment of data; consideration of the different needs and responses of endemic and epidemic countries and specific control plans; generation and sharing of informative case studies for neighboring countries; and tailoring national plans in the light of cross-border collaboration.
Finally, achieving equity demanded reaching high levels of coverage with both vector control and vaccination strategies and programs as well as covering all sectors of the population in need of protection. A prerequisite for equitable access to vaccines was the need and ability to negotiate lower prices of existing vaccines.
CONCLUSIONS
The Board concluded that there is a substantial knowledge gap on the epidemiology, clinical
presentation and pathogenesis of Zika virus infection and its potential implications for dengue
and the introduction of dengue vaccine. Further studies, including cohort and case-control
studies of Zika and dengue need to be undertaken. Long-term follow-up studies of Zika-infected
adults to assess neurological sequelae, and of infants born to Zika-infected women to assess
neurodevelopmental and other sequelae are needed. Given that some of these studies are
already being undertaken in the Americas, progress and results from these ongoing studies
should be more readily communicated in real time. Although current diagnostic tools have
limitations, seroprevalence studies of arbovirus infections incorporating testing for dengue,
Zika and chikungunya along with other relevant arboviruses such as yellow fever should be
conducted in conjunction with routine surveillance when possible.
Given the ongoing risk from new and existing Aedes-transmitted viruses, along with the
potential complications of co-circulation of these viruses, public health surveillance systems will
need to be strengthened to be able to detect such pathogens in a timely manner; and laboratory-
enhanced sentinel surveillance will need to be augmented in order to detect closely-related
pathogens. Countries are encouraged to establish or strengthen national reference laboratory
capacities and capabilities, with access to modern diagnostic tools (e.g., multiplex RT-PCR),
along with traditional virological and serological methods. More accurate and affordable
diagnostic assays are being developed, but will need to be validated in the field. These public
health systems should be strengthened in compliance with existing guidelines and in
conjunction with international organizations such as PAHO. Entomological surveillance should
be done in conjunction with disease surveillance.
The Board commended the collaborative work of the pharmaceutical industry with academia
and international, governmental and non-governmental organizations to develop vaccine
candidates for dengue and Zika, and for responding flexibly to the spread of Zika virus. The
Board also welcomed efforts on developing new insecticides and other vector control strategies.
New and existing tools for prevention and control, including vaccines and vector control
technologies, will need to be coordinated among different sectors within countries and with
international organizations. Any single tool or approach should be implemented in conjunction
with, not at the expense of, other approaches. To determine the appropriateness of different
interventions, the epidemiological impact of these methods should be measured systematically.
This information is more readily available for vaccines than for vector control methods and
combined approaches such as vaccine/vector control. Cost-effectiveness studies should also be
performed. Such studies need to be undertaken in order to inform public health authorities to
guide policy and decision-making. Adequate and sustained funding and resource allocation will
be critical to support such efforts.
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AmDPB Meeting Report
The Board also underlined the need for strategic and focused strategies to communicate
information about prevention and control of Aedes-transmitted diseases. Communication
should reach across different sectors targeting a broader audience beyond just the public health
sector, and to all levels of society. Strategic communication should expand beyond municipal,
country and regional programs to the global level, engaging senior policy-makers. However,
leadership at the country level will be vital.
This meeting was interpreted by Omnilingua
and the meeting report was prepared by Mr. David W. FitzSimons.
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Appendix 1: Agenda and Speakers
[Day 1] – Thursday August 3, 2017 Location: Room Pau Brasil (mezzanine floor)
8:20 – 9:00 am
Executive session of Dengue Prevention Board (closed session for Board Members)
Location: Room Ipê (mezzanine floor)
DPB members only (others will meet at “Pau Brasil” from 9am)
Opening Session
Location: Room Pau Brasil (mezzanine floor)
9:00 – 9:10 am Opening remarks
In-Kyu Yoon (GDAC Director)
João Paulo Toledo
(Brazil MoH)
9:10 – 9:35 am Global Aedes-transmitted diseases situation Duane J. Gubler (GDAC Chair)
Session I: Country Dengue/Zika situations
Facilitator: Jacqueline Lim
9:35 – 10:20 am
Country situation report on Zika and dengue situations (15
mins per presentation)
- Colombia
- Brazil
- Mexico
- Franklyn Prieto - João Paulo Toledo - Cuitláhuac
Ruiz - Matus
10:20 – 10:40 am Q&A and discussion Facilitator: Jacqueline Lim
10:40 – 11:00 am COFFEE BREAK
Session II: Epidemiology and Surveillance Facilitator: Jose F. Cordero
11:00 –11:30 am Dengue and Zika co-circulation in Brazil João Siqueira (Univ. of Goias)
11:30 –12:00 pm Neurologic complications of Zika in Brazil Wanderson Oliveira (FIOCRUZ)
12:00 – 12:15 pm Q&A and discussion Facilitator: Jose F. Cordero
12:15 – 1:45 pm LUNCH
Location: Aromatique Restaurant
1:45 –2:15 pm Differential diagnosis of dengue Luis A. Villar (Univ. Industrial de Santander)
2:15 – 2:45 pm Landscape of flavivirus diagnostics Ernesto Marques (FIOCRUZ)
2:45 – 3:00 pm Q&A and discussion Facilitator: Jose F. Cordero
3:00 – 3:20 pm COFFEE BREAK
Session III: Vaccines I Facilitator: Joao Siqueira
3:20 – 3:50 pm Preparatory studies for considering the implementation of
dengue vaccines in Brazil Marcelo Burattini (Univ. of São Paulo)
3:50 – 4:20 pm Dengue vaccine introduction in Parana state, Brazil Júlia Cordellini (Sesa)
4:20 – 4:50 pm Financing strategies for dengue and Zika vaccine Dagna Constenla (IVAC at JHSPH)
4:50 – 5:10 pm Q&A and discussion Facilitator: Joao Siqueira
7:00 –9:00 pm DINNER hosted by GDAC
Location: BARBACOA Itaim Restaurant( Rua Dr. Renato Paes de Barros, 65 – Itaim Bibi)
[Day 2] Friday August 4, 2017 Location: Room Pau Brasil (mezzanine floor)
Session IV: Vaccines II Facilitator: Anna Durbin
9:00 – 9:25 am Landscape of dengue & Zika vaccines Joachim Hombach (WHO)
9:25 – 9:50 am Pre-existing flavivirus immunity and enhancement Stephen Thomas (SUNY)
9:50 – 10:35 am
Issues in conducting dengue vaccine efficacy trials with Zika
co-circulation (15 mins per presentation)
1. Sanofi Pasteur 2. Butantan 3. Takeda
Presenters:
1. Ana Paula Perroud 2. Ricardo Palacios 3. Jeremy Brett
10:35 – 10:55 pm Q&A and discussion Facilitator: Anna Durbin
10:55 – 11:15 am COFFEE BREAK
Session V: Vector Control Facilitator: Jorge Mendez-Galvan
11:15 – 11:55 pm
Use of Wolbachia for biological control of dengue, Zika, and
Chikungunya
Eliminate Dengue in Brazil: Expansion plans
Jorge Osorio & Gabriel Ribeiro (Eliminate Dengue)
11:55 – 12:25 pm Integrated vector control/vaccine strategies Duane J. Gubler (GDAC Chair)
12:25 – 12:40 pm Q&A and discussion Facilitator: Jorge Mendez-Galvan
Session VI: Working Groups
12:40 – 1:40 pm WORKING LUNCH
*Sandwich bar will be set up in front of Pau Brasil
12:40 – 3:00 pm
WORKING GROUP sessions.
3 working groups will discuss considerations in different
topic areas and determine recommendations for
improvements in each topic area for countries to implement
with respect to dengue and Zika co-epidemics
1. Epidemiology and surveillance 2. Diagnostics 3. Prevention and Control
Facilitators for each working
group TBD
3:00 – 4:00 pm Presentation by each working group (10 min per
presentation + 10 min Q&A) Rapporteur for each group
4:00 – 5:00 pm COFFEE BREAK
Closing Session
4:00 – 5:00 pm Closed meeting among DPB members to prepare conclusions
5:00 – 5:30 pm Report by the Dengue Prevention Board Rapporteur for DPB
5:30 – 5:40 pm END - Closing remarks and adjourn Duane J. Gubler
(GDAC Chair)
Appendix 2: List of Meeting Participants BOARD MEMBERS Dr. Anabelle Alfaro Asesor temporario de atención
Grupo técnico de atención de
dengue OPS OMS
San Jose, Costa Rica
Dr. Aracely Alava Alprecht
(unable to attend)
Coordinator, Investigation and
Microbiological Diagnosis
Leopoldo Izquieta Perez National
Institute of Hygiene and Tropical
Medicine
Chair, Virology, Guayaquil
University
Ecuador
Dr. Juan Jose Amador
(unable to attend)
Boston University,
National coordinator and
Research Team Leader, Nicaragua
Dr. Antonio Arbo
Chief of Department of Research
and Teaching
Institute of Tropical Medicine
Asunción, Paraguay
Dr. Sulamita Brandão Barbiratto
Public Server
Ministry of Health/
Health Surveillance
Secretariat/National Dengue
Program Control
Brasilia, Brazil
Dr. Jorge Boshell
Director Biosafety Committee
Bone and Tissue Bank (Banco de
Huesos)
Biosafety Bone and Tissue Bank
Cosmas and Damian Foundation
Bogota, Colombia
Dr. Iris Villalobos de Chacon
(unable to attend)
Chief of Epidemiological Services
Hospital Central de Maracay
Av.Principal de la Floresta y Jose
Maria Varga Sector Las Delicias
Maracay, Estado Aragua,
Venezuela
Dr. José F. Cordero
Patel Distinguished Professor of
Public Health
University of Georgia
Athens, GA, USA
Dr. Delia A. Enria
(unable to attend)
Director, INEVH (Instituto Nacional
de Enfermedades Virales
Humanas)
Argentina
Dr. Eduardo Fernandez
Adjunct Professor
Community Health Sciences
Brock University
Canada
Dr. Maria Guadalupe Guzman
(unable to attend)
Head Virology Department
Director, PAHO
WHO Collaborating Center for
Viral Diseases
Pedro Kouri Tropical medicine
Institute
Autopista Novia del Mediodia
Havana, Cuba
Dr. Jorge F. Mendez-Galvan
Investigator/Researcher
Children's Hospital of Mexico
"Federico Gomez"
México D.F., MÉXICO
GDAC COLLABORATORS Dr. Ana F. Carvalho (unable to attend) Director, Special Projects Vaccine Advocacy and Education Sabin Vaccine Institute Washington D.C., USA [email protected] Dr. Dagna Constenla Associate Research Professor, Director of Economics and Finance International Vaccine Access Center John Hopkins Bloomberg School of Public Health Baltimore, Maryland, USA [email protected] Dr. Anna Durbin Associate Professor International Vaccine Access Center Johns Hopkins Bloomberg School of Public Health Baltimore, Maryland, USA [email protected] Dr. David FitzSimons Writer/Rapporteur Geneva, Switzerland [email protected] Dr. Duane J Gubler Chair Global Dengue and Aedes-Transmitted Diseases Consortium (GDAC) Professor Emeritus and Founding Director Signature Research Program in Emerging Infectious Disease Duke-NUS Medical School Singapore [email protected] Ms. Jacqueline Lim Research Scientist International Vaccine Institute Seoul, Korea [email protected]
Ms. Soo Hyun Rah Coordination Administrator International Vaccine Institute Seoul, Korea [email protected] Dr. Thomas W. Scott (unable to attend) Distinguished Professor University of California Davis, CA, USA [email protected] Dr. Annelies Wilder-Smith (unable to attend) Director Partnership for Dengue Control Professor, Infectious Diseases Lee Kong Chian School of Medicine Singapore [email protected] Dr. In-Kyu Yoon Director Global Dengue and Aedes-Transmitted Diseases Consortium (GDAC) Deputy Director General of Science International Vaccine Institute Seoul, Korea [email protected] INVITED GUESTS Dr. Durovni Betina
Researcher, Fiocruz
Rio de Janeiro, Brazil
Dr. Jeremy Brett
Senior Director Global Medical
Affairs
Vaccine Business Unit
Takeda Pharmaceuticals
International Ag
Zurich, Switzerland
Dr. Marcelo Burattini
Professor
University of Sao Paulo
Faculty of Medcine
Sao Paulo, Brazil
Dr. Roberta G. Carvalho
Mestre em Epidemiologia
Ministério da Saúde
Brasilia, Brazil
Dr. Júlia V. F. Cordellini
Superintendente de Vigilancia em
Saude
Sesa Secretaria de Saude do
Estado do Parana
Dr. Rodrigo DeAntonio-Suarez
Regional Epidemiology Director
GlaxoSmithKline plc.
Dr. Libia Milena Hernandez
Researcher/Coordinator Dengue
Vaccine clinical trials
Centro de Atención y Diagnóstico
de Enfermedades Infecciosas CDI
Bucaramanga, Colombia
Dr. Leyla Hernandez-Donoso
Takeda Pharmaceuticals
International Ag
eyla.a.hernandez-
Dr. Joachim Hombach
Senior Advisor in the Department
of Immunization
Vaccines and Biologicals
World Health Organization
Geneva, Switzerland
Dr. Sheila Homsani
Medical Director, Brazil
Sanofi Pasteur
Dr. Felipe Lorenzato
Takeda Pharmaceuticals
International Ag
Dr. Gusmao Marilia
Public Affairs & Advocacy
CoordinatorSanofi Pasteur
Dr. Ernesto Marques
Associate Professor, Infectious
Diseases and Microbiology
Public Health Researcher,
FIOCRUZ
Dr. Jose Cassio de Moraes
Professor
Santa Casa de São Paulo
Dr. Wanderson Kleber de Oliveira
Researcher
Center for Data Integration and
Knowledge for Health (CIDACS)
Fundação Oswaldo Cruz
(FIOCRUZ-Bahia)
Dr. Jorge Osorio
Director Government Relations-
Americas
Eliminate Dengue Program
m
Dr. Ricardo Palacios
Clinical R&D Manager
Division of Clinical Trials and
Pharmacovigilance
Instituto Butantan
São Paulo, Brazil
Dr. Cintia Parellada
Latin America Associate Regional
Medical Director
Merck
Dr. Roberta Piorelli
Product Safety Medical
Coordinator
Division of Clinical Trials and
Pharmacovigilance
Instituto Butantan
São Paulo, Brazil
Dr. Alexander Roberto Precioso
Director
Division of Clinical Trials and
Pharmacovigilance
Instituto Butantan
São Paulo, Brazil
.br
Dr. Franklyn Edwin Prieto
Alvarado
Public Health Surveillance Director
Instituto Nacional de Salud
Bogota, Colombia
Dr. Gabriel Sylvestre Ribeiro
Operations Manager
Eliminate Dengue Brazil- Fiocruz
Rio de Janeiro
gabriel.sylvestre@eliminatedengu
e.com
Dr. Cuitláhuac Ruiz – Matus
Director General of Epidemiology
Ministry of Health
Mexico City, Mexico
Dr. Ana Paula de Almeida Salles
Perroud
Regional Director of Clinical
Development Latin America
Sao Paulo, Brazil
Sanofi Pasteur
Dr. Gustavo Sánchez Tejeda
Director del Programa de
Enfermedades Transmitidas por
Vectores
CENAPRECE / Secretaria de Salud
Mexico City, Mexico
Mr. Joscelio A. Silva
Advisor
Ministério da Saúde
Brasilia, Brazil
Dr. Joao Bosco Siqueira Jr.
Adjunct Professor
Federal University of Goias
Goias, Brazil
Dr. Stephen Thomas
Chief, Division of Infectious
Diseases
SUNY Upstate Medical University
Syracuse, NY, USA
Dr. Beatriz Thomé
Clinical R&D Manager
Division of Clinical Trials and
Pharmacovigilance
Instituto Butantan
São Paulo, Brazil
Dr. João Paulo Toledo
Director of Communicable Disease
Ministry of Health
Brasilia, Brazil
Dr. Tazio Vanni Clinical R&D Manager
Division of Clinical Trials and
Pharmacovigilance
Instituto Butantan
São Paulo, Brazil
Dr. Luis A. Villar Director Universidad Industrial de Santander Bucaramanga, Colombia
Dr. Stephen Whitehead
Laboratory of Infectious Diseases
NIAID, NIH, DHHS
Bethesda, MD, USA
Dr. Bruno Zago
Specialist in Regulation and Health
Surveillance
Drug General Office – SUMED
National Health Surveillance
Agency – ANVISA
Brasilia, Brazil
Dr. Jean-Antoine Zinsou
Head of Public Affairs for new
vaccines – Global
Sanofi Pasteur