“Dengue in the time of Zika”

Meeting Report

2017 Americas Dengue Prevention Board Meeting

São Paolo, Brazil

3-4 August 2017

1

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,

2

AmDPB Meeting Report

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,

3

AmDPB Meeting Report

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)

4

AmDPB Meeting Report

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

ed c

ases

Epidemiological year and month

dengue chikunguña zika

5

AmDPB Meeting Report

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

0

20

40

60

80

100

120

ENER

O

FEB

RER

O

MA

RZO

AB

RIL

MA

YO

JUN

IO

JULI

O

AG

OST

O

SEP

TIEM

BR

E

OC

TUB

RE

NO

VIE

MB

RE

DIC

IEM

BR

E

ENER

O

FEB

RER

O

MA

RZO

AB

RIL

MA

YO

JUN

IO

2016 2017

Rat

e p

er 1

00

.00

0 N

V

6

AmDPB Meeting Report

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

7

AmDPB Meeting Report

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

8

AmDPB Meeting Report

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.

9

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.

10

AmDPB Meeting Report

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

11

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

12

AmDPB Meeting Report

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

13

AmDPB Meeting Report

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.

14

AmDPB Meeting Report

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

15

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

16

AmDPB Meeting Report

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.

17

AmDPB Meeting Report

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

18

AmDPB Meeting Report

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

19

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.

20

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.

21

AmDPB Meeting Report

1 Ministério da Saúde, Secretaria de Vigilância em Saúde. Monitoramento dos casos e óbitos de febre amarela

no Brasil. COES – Febre Amarela, Informe, Nº 39/2017 (http://portalarquivos.saude.gov.br/images/pdf/2017/ maio/04/COES-FEBRE-AMARELA---INFORME-39---Atualizacao-em-04maio2017.pdf, accessed 9 August 2017). 2 Worobey M. Epidemiology: molecular mapping of Zika spread. Nature, 2017, 15 June, 546:355-357

doi:10.1038/nature22495 (http://www.nature.com/nature/journal/v546/n7658/full/nature22495.html, accessed 7 August 2017), and references therein. 3 Metsky HC, Matranga CB, Wohl S et al. Zika virus evolution and spread in the Americas. Nature, 2017,

546:411-415 doi 10.1038/nature22402 (http://www.nature.com/nature/journal/v546/n7658/ full/nature22402.html, accessed 9 August 2017). 4 Kleber de Oliveira W, Araújo de França GV, Carmo EH et al. Infection-related microcephaly after the 2015 and

2016 Zika virus outbreaks in Brazil: a surveillance-based analysis. Lancet, June 21, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31368-5 (https://www.researchgate.net/publication/317778795_ Infection-related_microcephaly_after_the_2015_and_2016_Zika_virus_outbreaks_in_Brazil_A_surveillance-based_analysis, accessed 12 August 2017). 5 Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde, Secretaria de Atenção à Saúde. Orientações

integradas de vigilância e atenção à saúde no âmbito da Emergência de Saúde Pública de Importância Nacional: procedimentos para o monitoramento das alterações no crescimento e desenvolvimento a partir da gestação até a primeira infância, relacionadas à infecção pelo vírus Zika e outras etiologias infeciosas dentro da capacidade operacional do SUS [recurso eletrônico] / Ministério da Saúde, Secretaria de Vigilância em Saúde, Secretaria de Atenção à Saúde – Brasília: Ministério da Saúde, 2017 (http://portalarquivos.saude.gov.br/ images/pdf/2016/dezembro/12/orientacoes-integradas-vigilancia-atencao.pdf, accessed 8 August 2017). 6 Secretaria de Vigilância em Saúde, Ministério da Saúde. Monitoramento dos casos de dengue, febre de

chikungunya e febre pelo vírus Zika até a Semana Epidemiológica 25, 2017. Boletim Edipemiológico, 2017, 48(20), 1-10 (http://portalarquivos.saude.gov.br/images/pdf/2017/julho/25/Boletim-2017_020-Monitoramento-dos-casos-de-dengue-febre-de-chikungunya-e-febre-pelo-Zika.pdf, accessed 8 August 2017). 7 http://www.ins.gov.co/lineas-de-accion/Subdireccion-Vigilancia/sivigila/Paginas/sivigila.aspx, accessed 9

August 2017). 8 Beltrán-Silva SL, Chacón-Hernández SS, Moreno-Palacios E, Pereyra-Molina JA. Clinical and differential

diagnosis: Dengue, chikungunya and Zika: Diagnóstico clínico y diferencial: dengue, chikunguña y zika. Revista Médica del Hospital General de México, 2016, (https://doi.org/10.1016/j.hgmx.2016.09.011, accessed 7 August 2017). 9 Lessler J, Chaisson LH, Kucirka LA et al. Assessing the global threat from Zika virus. Science 14 Jul 2016:

aaf8160 DOI: 10.1126/science.aaf8160

(http://science.sciencemag.org/content/early/2016/07/13/science.aaf8160.full, accessed 7 August 2017). 10

For a recent review from Mexico, see Beltrán-Silva SL, Chacón-Hernández SS, Moreno-Paalacios E, Pereyra-Molina JA. Clinical and differential diagnosis: dengue, chikungungya and Zika. Revista Médica del Hospital Geneeral de México, 2016 (https://doi.org/10.1016/j.hgmx.2016.09.011, accessed 18 August 2017). 11

Chen CH, Huang YC, Kuo KC, Li CC. Clinical features and dynamic ordinary laboratory tests differentiating dengue fever from other febrile illnesses in children. Journal of Microbiology, Immunology and Infection, 2017, DOI: (http://dx.doi.org/10.1016/j.jmii.2016.08.018, accessed 9 August 2017). 12

Tuan NM, Ho TN, Chau NVV, Simmons C. An evidence-based algorithm for early prognosis of severe dengue

in the outpatient setting. Clinical Infectious Diseases 64(5, December 2016), doi: 10.1093/cid/ciw863. 13

Braga JU, Bressan C, Dalvi APR et al. Accuracy of Zika virus disease case definition during simultaneous Dengue and Chikungunya epidemics. PLoS One. 2017 Jun 26;12(6):e0179725. 14

Balmaseda A, Stettler K, Medialdea-Carrera R et al. Antibody-based assay discriminates Zika virus infection from other flaviviruses. Proceedings of the National Academy of Sciences, 2017, 114(31):8384–8389, doi: 10.1073/pnas.1704984114 15

Halstead SB. Biologic evidence required for Zika disease enhancement by dengue antibodies. Emerging Infectious Diseases 2017, 23(4): 569-573. (https://dx.doi.org/10.3201/eid2304.161879, https://wwwnc.cdc.gov/eid/article/23/4/16-1879_article, accessed 11 August 2017). 16

Constenla D, Clark S. Financing dengue vaccine introduction in the Americas: challenges and opportunities. Expert Review of Vaccines, 2016, 15(4):547-559, DOI: 10.1586/14760584.2016.1134329 (http://www-personal.umich.edu/~srisawat/temp/Financing.pdf, accessed 10 August 2017).

22

AmDPB Meeting Report

17

WHO Vaccine Pipeline Tracker, (http://www.who.int/immunization/research/vaccine_pipeline_tracker_ spreadsheet/en/, accessed 10 August 2017). 18

Vannice KS, Durbin A, Hombach J. Status of vaccine research and development of vaccines for dengue. Vaccine, 2016, 34:2934-2938 (http://www.nitag-resource.org/uploads/media/default/ 0001/03/a247f1650f6b35e6ddc24e6c67e21c2d4a24f004.pdf, accessed 11 August 2017). 19

WHO. Dengue vaccine: WHO position paper – July 2016. Weekly Epidemiological Record, 2016, 91(30):349-364 (www.who.int/wer/2016/wer9130.pdf?ua=1, accessed 11 August 2017). 20

Available through the following page on the WHO web site: (http://www.who.int/immunization/research/ development/dengue_serosurveys/en/, accessed 11 August 2017). 21

WHO/UNICEF Zika virus (ZIKV) vaccine target product profile (TPP): vaccine to protect against congenital Zika syndrome for use during an emergency. Updated February 2017 (http://www.who.int/immunization/research/development/WHO_UNICEF_Zikavac_TPP_Feb2017.pdf, accessed 11 August 2017). 22

Aliota MT, Walker EC, Uribe Yepes A, Dario Velez I, Christensen BM, Osorio JE (2016) The wMel Strain of Wolbachia Reduces Transmission of Chikungunya Virus in Aedes aegypti. PLoS Negl Trop Dis 10(4): e0004677. https://doi.org/10.1371/journal.pntd.0004677 23

van den Hurk, Hall-Medelin S, Pyke AT et al. impact of Wolbachia on infection with chikungunya and yellow fever viruses in the mosquito vector Aedes aegypti. PLOS Neglected Tropical Diseases 2012 24

Reiner RC Jr, Achee N, Barrera R, Burkot TR, Chadee DD, Devine GJ, et al. (2016) Quantifying the epidemiological impact of vector control on dengue. PLoS Negl Trop Dis 10(5): e0004588. (https://doi.org/10.1371/journal.pntd.0004588, http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004588#sec012, accessed 30 June 2017).

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

anabellealfaro@gmail.com

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

aracelyalava@gmail.com

Dr. Juan Jose Amador

(unable to attend)

Boston University,

National coordinator and

Research Team Leader, Nicaragua

amadorjuan2430@yahoo.com

Dr. Antonio Arbo

Chief of Department of Research

and Teaching

Institute of Tropical Medicine

Asunción, Paraguay

antonioarbo@hotmail.com

Dr. Sulamita Brandão Barbiratto

Public Server

Ministry of Health/

Health Surveillance

Secretariat/National Dengue

Program Control

Brasilia, Brazil

sulamita.barbiratto@saude.gov.br

Dr. Jorge Boshell

Director Biosafety Committee

Bone and Tissue Bank (Banco de

Huesos)

Biosafety Bone and Tissue Bank

Cosmas and Damian Foundation

Bogota, Colombia

jboshell@cydbank.org

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

irisvillalobos2004@yahoo.es

Dr. José F. Cordero

Patel Distinguished Professor of

Public Health

University of Georgia

Athens, GA, USA

jcordero@uga.edu

Dr. Delia A. Enria

(unable to attend)

Director, INEVH (Instituto Nacional

de Enfermedades Virales

Humanas)

Argentina

deliaenria@gmail.com

Dr. Eduardo Fernandez

Adjunct Professor

Community Health Sciences

Brock University

Canada

efernandez@brocku.ca

eduardofmil@yahoo.com

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

lupe@ipk.sld.cu

Dr. Jorge F. Mendez-Galvan

Investigator/Researcher

Children's Hospital of Mexico

"Federico Gomez"

México D.F., MÉXICO

jorge.f.mendez@gmail.com

GDAC COLLABORATORS Dr. Ana F. Carvalho (unable to attend) Director, Special Projects Vaccine Advocacy and Education Sabin Vaccine Institute Washington D.C., USA ana.carvalho@sabin.org 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 dconste1@jhu.edu Dr. Anna Durbin Associate Professor International Vaccine Access Center Johns Hopkins Bloomberg School of Public Health Baltimore, Maryland, USA adurbin1@jhu.edu Dr. David FitzSimons Writer/Rapporteur Geneva, Switzerland fitzsimonsd@gmail.com 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 duane.gubler@duke-nus.edu.sg Ms. Jacqueline Lim Research Scientist International Vaccine Institute Seoul, Korea kalim@ivi.int

Ms. Soo Hyun Rah Coordination Administrator International Vaccine Institute Seoul, Korea soorah@ivi.int Dr. Thomas W. Scott (unable to attend) Distinguished Professor University of California Davis, CA, USA twscott@ucdavis.edu Dr. Annelies Wilder-Smith (unable to attend) Director Partnership for Dengue Control Professor, Infectious Diseases Lee Kong Chian School of Medicine Singapore awilder-smith@ntu.edu.sg Dr. In-Kyu Yoon Director Global Dengue and Aedes-Transmitted Diseases Consortium (GDAC) Deputy Director General of Science International Vaccine Institute Seoul, Korea inkyu.yoon@ivi.int INVITED GUESTS Dr. Durovni Betina

Researcher, Fiocruz

Rio de Janeiro, Brazil

betina.durovni@fiocriz.br

Dr. Jeremy Brett

Senior Director Global Medical

Affairs

Vaccine Business Unit

Takeda Pharmaceuticals

International Ag

Zurich, Switzerland

jeremy.brett@takeda.com

Dr. Marcelo Burattini

Professor

University of Sao Paulo

Faculty of Medcine

Sao Paulo, Brazil

mnburatt@gmail.com

Dr. Roberta G. Carvalho

Mestre em Epidemiologia

Ministério da Saúde

Brasilia, Brazil

roberta.carvalho@saude.gov.br

Dr. Júlia V. F. Cordellini

Superintendente de Vigilancia em

Saude

Sesa Secretaria de Saude do

Estado do Parana

julia.cordellini@sesa.pr.gov.br

Dr. Rodrigo DeAntonio-Suarez

Regional Epidemiology Director

GlaxoSmithKline plc.

rodrigo.d.deantonio@gsk.com

Dr. Libia Milena Hernandez

Researcher/Coordinator Dengue

Vaccine clinical trials

Centro de Atención y Diagnóstico

de Enfermedades Infecciosas CDI

Bucaramanga, Colombia

libiamilenah@hotmail.com

Dr. Leyla Hernandez-Donoso

Takeda Pharmaceuticals

International Ag

eyla.a.hernandez-

donoso@takeda.com

Dr. Joachim Hombach

Senior Advisor in the Department

of Immunization

Vaccines and Biologicals

World Health Organization

Geneva, Switzerland

hombachj@who.int

Dr. Sheila Homsani

Medical Director, Brazil

Sanofi Pasteur

Sheila.Homsani@sanofi.com

Dr. Felipe Lorenzato

Takeda Pharmaceuticals

International Ag

Felipe.Lorenzato@takeda.com

Dr. Gusmao Marilia

Public Affairs & Advocacy

CoordinatorSanofi Pasteur

Marilia.Gusmao@sanofi.com

Dr. Ernesto Marques

Associate Professor, Infectious

Diseases and Microbiology

Public Health Researcher,

FIOCRUZ

marques@pitt.edu

Dr. Jose Cassio de Moraes

Professor

Santa Casa de São Paulo

jcassiom@uol.com.br

Dr. Wanderson Kleber de Oliveira

Researcher

Center for Data Integration and

Knowledge for Health (CIDACS)

Fundação Oswaldo Cruz

(FIOCRUZ-Bahia)

wkoliveira@gmail.com

Dr. Jorge Osorio

Director Government Relations-

Americas

Eliminate Dengue Program

jorge.osorio@eliminatedengue.co

m

Dr. Ricardo Palacios

Clinical R&D Manager

Division of Clinical Trials and

Pharmacovigilance

Instituto Butantan

São Paulo, Brazil

ricardo.palacios@butantan.gov.br

Dr. Cintia Parellada

Latin America Associate Regional

Medical Director

Merck

cintia.parellada@merck.com

Dr. Roberta Piorelli

Product Safety Medical

Coordinator

Division of Clinical Trials and

Pharmacovigilance

Instituto Butantan

São Paulo, Brazil

roberta.piorelli@butantan.gov.br

Dr. Alexander Roberto Precioso

Director

Division of Clinical Trials and

Pharmacovigilance

Instituto Butantan

São Paulo, Brazil

alexandre.precioso@butantan.gov

.br

Dr. Franklyn Edwin Prieto

Alvarado

Public Health Surveillance Director

Instituto Nacional de Salud

Bogota, Colombia

fprieto@ins.gov.co

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

cuitlahuac.ruiz@salud.gob.mx

Dr. Ana Paula de Almeida Salles

Perroud

Regional Director of Clinical

Development Latin America

Sao Paulo, Brazil

Sanofi Pasteur

AnaPaula.Perroud@sanofi.com

Dr. Gustavo Sánchez Tejeda

Director del Programa de

Enfermedades Transmitidas por

Vectores

CENAPRECE / Secretaria de Salud

Mexico City, Mexico

gsancheztejeda@gmail.com

Mr. Joscelio A. Silva

Advisor

Ministério da Saúde

Brasilia, Brazil

joscelio.silva@saude.gov.br

Dr. Joao Bosco Siqueira Jr.

Adjunct Professor

Federal University of Goias

Goias, Brazil

siqueirajb@gmail.com

Dr. Stephen Thomas

Chief, Division of Infectious

Diseases

SUNY Upstate Medical University

Syracuse, NY, USA

thomstep@upstate.edu

Dr. Beatriz Thomé

Clinical R&D Manager

Division of Clinical Trials and

Pharmacovigilance

Instituto Butantan

São Paulo, Brazil

beatriz.thome@butantan.gov.br

Dr. João Paulo Toledo

Director of Communicable Disease

Ministry of Health

Brasilia, Brazil

Joao.toledo@saude.gov.br

Dr. Tazio Vanni Clinical R&D Manager

Division of Clinical Trials and

Pharmacovigilance

Instituto Butantan

São Paulo, Brazil

tazio.vanni@butantan.gov.br

Dr. Luis A. Villar Director Universidad Industrial de Santander Bucaramanga, Colombia

luisangelvillarc@gmail.com

Dr. Stephen Whitehead

Laboratory of Infectious Diseases

NIAID, NIH, DHHS

Bethesda, MD, USA

swhitehead@niaid.nih.gov

Dr. Bruno Zago

Specialist in Regulation and Health

Surveillance

Drug General Office – SUMED

National Health Surveillance

Agency – ANVISA

Brasilia, Brazil

BRUNO.DINIZ@anvisa.gov.br

Dr. Jean-Antoine Zinsou

Head of Public Affairs for new

vaccines – Global

Sanofi Pasteur

Jean-Antoine.Zinsou@sanofi.com