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Expert Review of Vaccines

ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20

Points for Consideration for dengue vaccineintroduction – recommendations by the DengueVaccine Initiative

Jacqueline Kyungah Lim, Yong-Seok Lee, Annelies Wilder-Smith, GeorgesThiry, Richard Mahoney & In-Kyu Yoon

To cite this article: Jacqueline Kyungah Lim, Yong-Seok Lee, Annelies Wilder-Smith, GeorgesThiry, Richard Mahoney & In-Kyu Yoon (2016) Points for Consideration for dengue vaccineintroduction – recommendations by the Dengue Vaccine Initiative, Expert Review of Vaccines,15:4, 529-538, DOI: 10.1586/14760584.2016.1129279

To link to this article: http://dx.doi.org/10.1586/14760584.2016.1129279

Accepted author version posted online: 10Dec 2015.Published online: 06 Jan 2016.

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REVIEW

Points for Consideration for dengue vaccine introduction – recommendationsby the Dengue Vaccine InitiativeJacqueline Kyungah Lima, Yong-Seok Leea, Annelies Wilder-Smithb, Georges Thiryc, Richard Mahoneyd andIn-Kyu Yoona

aInternational Vaccine Institute – Dengue Vaccine Initiative, Seoul, The Republic of Korea; bGlobal Health and Vaccinology Programme, LeeKong Chian School of Medicine, Novena Campus, Singapore; cSenergues Consult, Vaccines, Toulouse, France; dRTM Associates, Sedona, AZ,USA

ABSTRACTDengue is a public health problem in the tropics and subtropics. There are several vaccinecandidates in clinical development. However, there may be gaps in the new vaccine introductionafter vaccine licensure before it becomes available in developing countries. In anticipation of thefirst dengue vaccine candidate to be licensed, Dengue Vaccine Initiative (DVI) and, its predeces-sor, Pediatric Dengue Vaccine Initiative (PDVI) have been working on points for consideration toaccelerate evidence-based dengue vaccine introduction, once a vaccine becomes available. Inthis paper, we review the history of PDVI and its successor, the DVI, and elaborate on the pointsof consideration for dengue vaccine introduction.

ARTICLE HISTORYReceived 5 October 2015Accepted 4 December 2015Published online 4 January2016

KEYWORDSDengue; vaccine;introduction; DengueVaccine Initiative; points forconsideration

Introduction

Historically, there have been major gaps in the intro-duction of new vaccines between industrialized anddeveloping countries. Often, 10–25 years pass before anew vaccine reaches the poor in developing countries,with good examples being the introduction of hepatitisB and Haemophilus influenzae (HiB) vaccines. The rea-sons for these major delays between vaccine licensureand availability in developing countries are complex.[1]For example, the delay for HiB vaccine introduction wasattributed to lack of data on burden of disease orvaccine impact, inadequate supply, cost and financinglimitations, and lack of political will.[2] To address theseissues, the HiB vaccine consortium was established.Experience of the HiB Initiative demonstrates that,despite various challenges, acceleration of new vaccineintroduction is feasible and that the gap in introductionbetween industrialized and developing countries notonly should be but can be narrowed.[2]

Dengue is a high-burden disease that disproportio-nately affects countries in the tropics and subtropics,many of which have limited health-care resources.[3]Given the progress of the past decade to develop adengue vaccine, and in anticipation of the first denguevaccine candidate to be licensed,[4–6] it is important toaddress vaccine introduction issues to reduce the delay inthe vaccine reaching the poor. Partly to deal with vaccine

introduction, the Pediatric Dengue Vaccine Initiative(PDVI), a consortium among academic institutions andpublic health agencies, was established in 2001.

Applying lessons learnt from the HiB initiative thathighlighted the need for communication and advocacy,research and surveillance, and strategic coordination,PDVI set out to identify Points for Consideration to accel-erate evidence-based dengue vaccine introduction, oncea vaccine becomes available. In this paper, we review thehistory of PDVI and its successor, the Dengue VaccineInitiative (DVI), and elaborate on the points of considera-tion for dengue vaccine introduction.[1]

Dengue and dengue vaccines

Dengue, a mosquito-borne flavivirus infection causedby four related but antigenically distinct dengue viruses(DENVs, serotypes 1–4), is a major and rapidly increas-ing public health problem of the tropics and subtropics.Dengue vaccine research and development has beenongoing since the 1940s, but several major hurdleshave hampered the rapid development of such a vac-cine, which includes overall poor funding for denguecompared to other vaccines and scientific challengessuch as the lack of an appropriate animal model, poorunderstanding of correlates of protection, concernsabout immune enhancement, and viral interference intetravalent vaccine combinations.[7–10] However, in

CONTACT Jacqueline Kyungah Lim kalim@IVI.INT

EXPERT REVIEW OF VACCINES, 2016VOL. 15, NO. 4, 529–538http://dx.doi.org/10.1586/14760584.2016.1129279

© 2016 Taylor & Francis

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the past decade, major progress has been achieved,with three leading live-attenuated vaccine candidatesin phase 2 or 3 clinical trials. The most advanced vac-cine, developed by Sanofi Pasteur, is a tetravalent live-attenuated vaccine in which key DENV genes areinserted into a yellow fever virus backbone.

The Dengue Vaccine Initiative

Initially, the goal of the PDVI was to accelerate the devel-opment, evaluation, and introduction of safe, effective, andaffordable dengue vaccines in endemic countries, espe-cially for the poor. When the PDVI began in 2001, (1) veryfew dengue vaccine candidates were in clinical develop-ment, (2) no modern clinical guidelines or clear regulatorypathways were available to guide development, and (3)there was limited information on the magnitude of thedengue disease burden and related economic costs. Inrecognition of the gaps, several activities were undertakenby the PDVI. The PDVI supported the development ofguidelines for the conduct of dengue vaccine clinical trialswith the goal of facilitating regulatory licensure. PDVI sup-ported preclinical development of dengue vaccine candi-dates, development of vaccine trial sites, generation of fielddata for improved estimates of national dengue diseaseburden, and measurement of cost of dengue illness inseveral countries. Recognizing that vaccine introductionneeds to include advocacy, PDVI also prepared and disse-minated information for global, regional, and national pol-icymakers and opinion leaders to achieve increasedawareness about dengue and dengue vaccines. One ofPDVI’s initiatives was the creation of two DenguePrevention Boards – one for Latin America and one forAsia – which would consist of regional dengue expertsthat meet regularly and issue reports on dengue-relatedtopics targeted to public health professionals in dengue-endemic countries. After PDVI program termination in

2010, in anticipation of the licensure of the world’s firstdengue vaccine, DVI was built on the momentum andcapabilities established by the PDVI. In 2011, the DVI wasreorganized as a consortium of four partners: InternationalVaccine Institute (IVI), Initiative for Vaccine Research of theWorld Health Organization (WHO), International VaccineAccess Center of Johns Hopkins University School ofPublic Health, and Sabin Vaccine Institute. With the sameoverall program goal, DVI continued as a focused programwith twomain objectives: (1) to generate data for decision-making process and (2) to conduct policy- and access-related activities to facilitate dengue vaccine introduction.

Dengue Prevention Boards

As part of its policy- and access-related activities, a keyachievement of DVI has been to maintain the momentumof dialogue on dengue vaccine development using theestablished Asia-Pacific Dengue Prevention Board(APDPB) and the Americas Dengue Prevention Board(AmDPB). The regional Dengue Prevention Boards – onefor the Americas and one for Asia – were established in2007 by PDVI to address key issues, share information, andmake recommendations concerning best practices relatedto dengue control, as well as to advocate for the control ofdengue through immunization within their regions andcountries. The Boards, which meet once or twice a year,consist of medical and public health experts and opinionleaders from 11 countries in Asia and 12 countries in theAmericas. The 11 countries represented on the APDPB areAustralia, Cambodia, India, Indonesia, Malaysia, Myanmar,the Philippines, Singapore, Sri Lanka, Thailand, andVietnam. The 12 countries represented on the AmDPB areArgentina, Brazil, Colombia, Costa Rica, Cuba, Ecuador,Honduras, Mexico, Nicaragua, Paraguay, Puerto Rico(USA), and Venezuela. Figure 1 shows the countries repre-sented on the DVI DPBs.

Americas Dengue Prevention Boards

Asia-PacificDengue Prevention Boards

Figure 1. Countries represented on Dengue Vaccine Initiative’s Dengue Prevention Boards of the Asia-Pacific and the Americasregions.

530 J. K. LIM ET AL.

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Planning for vaccine introduction

By late 2011, progress with the Sanofi Pasteur vaccineled to the conclusion that the vaccine might be licensedin a few years. Sanofi Pasteur met with the DVI andnoted that it would be able to produce only about 100million doses per year (sufficient for about 33 millionchildren and young adults – a very small proportion ofthose in need) and asked whether DVI would undertakea process to identify those countries that would be thefirst to introduce as well as develop strategies for cost-effective introduction. DVI agreed to take on this taskseeing itself as a neutral third party concerned withpublic health and with an established track record ofpublic–private collaboration. In June 2012, the APDPBmet in Bangkok, Thailand, to develop Points forConsideration that would provide a framework for coun-tries to decide about their interest in and capability toundertake the introduction of a first licensed denguevaccine.[11] Participants in the meeting included repre-sentatives of Ministries of Health of seven countries ofthe APDPB, research and donor institutions (AFRIMS, Bill& Melinda Gates Foundation), vaccine and diagnosticsindustries (GlaxoSmithKline, Inviragen, Merck, SanofiPasteur, and Standard Diagnostics), and DVI. Similarly,the AmDPB meeting was held in Bucaramanga,Colombia, in July 2012 to consider and contribute tothe draft Points for Consideration developed at theAPDPB meeting.[12] For the AmDPB meeting, the parti-cipants were representatives of Ministries of Health ofeight countries of the AmDPB, research and donor insti-tutions, the Pan American Health Organization (PAHO,WHO Regional Office for the Americas), the GAVIAlliance, the Carlos Slim Health Institute, public sectorvaccine producers (Instituto Butantan), private sectorvaccine producers (GlaxoSmithKline, Inviragen, Merck,Sanofi Pasteur), and DVI.

An initial step was to identify the key capabilitiesthat countries would need to introduce a vaccine effec-tively. These capabilities were in the areas of (1) regu-latory affairs, (2) evidence for decision-making, (3)impact modeling, (4) immunization systems, (5)demand and financing, and (6) postlicensure studies.For each area, the DPB members as well as meetingparticipants discussed specific points that may be con-sidered by the country before making a decisionregarding dengue vaccine introduction. The initial setsof the DVI recommendations from the two regional DPBmeetings are summarized in Table 1.

Based on the Points for Consideration and assess-ment of the capabilities of countries, seven countrieswere identified as potential early adopters: Brazil,Colombia, and Mexico in the Americas and Indonesia,

Malaysia, the Philippines, and Thailand in Asia. Thedevelopment of the Points for Consideration and theidentification of the potential early adopter countriesmet the goals identified in the discussions betweenSanofi Pasteur and DVI in late 2011 and represented amajor achievement of the DVI. Such advance prelicen-sure collaborative vaccine introduction planning hadnever previously been done by a public sector group.

In September of 2012, the phase 2b trial results ofSanofi Pasteur’s dengue vaccine candidate werereleased.[13] The trial was based on 4002 Thai schoolchildren between 4 and 11 years of age. The reportedefficacy was 30.2% with 95% confidence interval from−13.4% to 56.6% differing by serotype, with disappoint-ing results for serotype 2.[7,13,14] Such results led toseveral uncertainties and confirmed the complexity andchallenges of dengue vaccine development.[15] Withthe need for data from larger efficacy trials andlonger-term follow-up before introduction could belaunched, it was decided to await the results of large-scale phase 3 trials taking place in five countries in LatinAmerica and five countries in Asia.[16,17] Further dis-cussion on vaccine introduction was postponed.

In July 2014, phase 3 trial results from Asia were pub-lished, followed by phase 3 trial results from the Americasin November 2014.[16,17] These studies demonstrated thatthe dengue vaccine candidate provided up to 60% protec-tion against dengue and up to 80% against hospitalizationsdue to dengue in the first year of follow-up after theprimary series, although serotype-specific efficacy variedwidely. In view of these data, DVI convened a meeting ofthe APDPB in November 2014, in Seoul, Korea, for thepurpose of (1) openly discussing countries’ perspectivesfor licensing and introducing dengue vaccines in the con-text of the ‘Points for Consideration’ earlier developed bythe APDPB and AmDPB; and (2) reviewing the denguevaccine phase 3 clinical trial results, and the progress ofclinical development with other candidate vaccines, andthe mathematical modeling of the potential impact ofvaccination on dengue.[18] The meeting allowed for infor-mation sharing from all vaccine manufacturers on thedevelopment status of their candidate vaccines and fordiscussion with modelers on the latest impact predictionsof dengue vaccination. The DPB members provided theirperspectives on the prospects for dengue vaccine introduc-tion and use in their countries, including integration withvector control, and they highlighted specific challengesand needs for decisions. A similar meeting was arrangedfor the AmDPB members in Bogota, Colombia, in March2015 to revisit the minimum requirements for successfullylaunching a dengue vaccination program.[19] When thePoints for Consideration were revisited in 2014 and 2015, alarge number of additional matters were identified for each

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Table 1. Points for Consideration in preparation for vaccine introduction developed in 2012.Points for Consideration (2012)

1. Regulatory Countries should consider capacity of the National Regulatory Authorities to:oversee Phase 3 and 4 trials; make licensing decisions for innovative products based on scientific review; evaluatedata on target populations and dosing schedules; develop and validate lot release testing for innovative vaccines;recognize and assure current Good Manufacturing Practices (cGMP); investigate Adverse Events FollowingImmunization from clinical trials or catch-up campaigns; perform long-term safety monitoring; and self-assessperformance of the National Regulatory Agency (NRA)Countries should also consider:involving WHO recognized regulators to discuss licensing decisions; a gap analysis of the NRA; the NRA’swillingness to accord priority review; the NRA’s ability to assess manufacturers’ risk management plans and countryspecific issues (GMOs, etc.); and coordination between the National Immunization Technical Advisory Group(NITAG) and NRA

2. Evidence for decision-making Countries should have the ability to undertake or participate in:Epidemiological surveillanceEvidence of burden of dengue disease, both outpatient and inpatient, including the incidence, age andgeographical distribution, serotypes in circulation and seroprevalence in key epidemic locales; mortality anddisease severity data; and adequate epidemiological and laboratory capabilities to carry out appropriate denguesurveillanceEconomic studiesDirect cost of illness by severity, in-patient/out-patient care, public/private sectors, and individuals/households;indirect cost of illness; outbreak costs; willingness to pay; cost-utility; and cost of preventionPolicy studiesPolicy review of the importance of the disease; an assessment of the risk-benefits; an assessment of theprogrammatic challenges in affordability and sustainability/logistics and supplies; an assessment of the strategicoptions in routine and mass immunization/scheduling/co-administration/target age groupsSocial studiesConduct and evaluation of Knowledge, Attitude and Practices (KAP) studiesModelingDengue virus transmission; age-specific disease attack rates; immunization implementation costs; and cost savingImpact assessmentsPublic health impacts and vaccine effectiveness after vaccine introduction through uniform study designs andprotocols

3. Impact modeling Countries should consider:The potential applications of modelingIntegrating information from multiple sources of data to provide a transparent summary of the current denguesituation; developing optimal immunization strategies including routine vaccination and catch-up programs;determining target groups for vaccination, Phase 4 study design and demand forecasting; assessing economicimpacts from immunization, epidemiological impacts from immunization and the synergistic impacts of otherprevention/control strategies (vector control)The country’s ability to conduct impact modelingVector density for the locale being modeled; incidence of cases and deaths by age and gender; serotype-specificsusceptibility profile by age; natural history of infection including incubation period, infectious period and inter-serotype interaction; historical distribution of each serotype by age; corrective factors to ensure that under- orover-reporting of vaccination is accounted for; impacts of other types of interventions such as vector controlactivities; overall and serotype-specific vaccination factors

4. Immunization systems Countries should consider:- The recommendations of NITAG- The strategy for vaccine introduction- The budget for a dengue vaccine- The capacity for immunization surveillance- The capacity for monitoring and evaluation- The capacity of the cold chain and logistics management- The capacity of the information system- The capacity of the communication systems- Training- Cross-sector collaborations

5. Demand and financing DemandCountries should consider:Historical rollout data; previous experience with mass immunization campaigns or with a vaccine outside of the EPIschedule; and the functioning of management and delivery systems.FinancingCountries should consider:The budget line-item for a dengue vaccine; the fiscal space to increase the immunization budget; the fiscal spacefor monitoring and evaluation; the budget for implementation and delivery of a dengue immunization program;the fiscal space to maintain financing for existing vector control; experience in the coordination of budgets acrossministries; experience with price negotiations.

6. Postlicensure/demonstration projects Countries must:- Have national support and community acceptance- Have the technical capacity, resources, and desire to evaluate safety and effectiveness- Be willing to share outputs of studies- Have functioning technical collaborations

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of the Points for Consideration from 2012 and are pre-sented in Table 2.

The ‘Points for Consideration for First Introductions ofDengue Vaccines’ reported in 2012 were designed to pro-vide a framework to assist policymakers and nationalimmunization program managers to determine the neces-sary capabilities for first introductions of a dengue vaccineand to provide guidance to other countries wishing tosubsequently adopt dengue vaccines. In 2014 and 2015,the DPBs gathered to refine and adapt the Points forConsideration based on the newly available informationaround dengue vaccine development and mathematicalmodels. In general, the original set of Points forConsideration was thought to be too demanding andneeded to be simplified. Also, it was emphasized that thecountries should work together to share and generate keyinformation, such as efficacy and safety. Among the sixareas, the meetings focused on three areas: (1) evidencefor decision-making, (2) impact modeling, and (3) immuni-zation systems. Regarding the regulatory aspects, paralleldiscussions among representatives of the NationalRegulatory Authorities (NRAs) had continued with theobjective of harmonizing the review process among differ-ent countries interested in dengue vaccine introduction.

Progress on regulatory matters

These regulatory-related discussions progressed at sepa-rate meetings twice per year among the NRAs of the short-listed seven countries that were likely to consider earlyintroduction of dengue vaccines. The regular meetingsbrought together NRAs from Malaysia, Indonesia,Thailand, the Philippines, Brazil, Colombia, and Mexico,and these were considered as major contributions of DVI.Two meetings were organized in 2013 in Brasilia in Apriland in Bangkok in October. The meetings established aplatform for collaboration among regulators and for inter-action between vaccine developers and regulators, consid-ering the preparations for a joint evaluation of theregistration dossier of the Sanofi Pasteur vaccine. Withthe main objective to strengthen capacity of the NRAs ofthe selected countries, the meetings continued in 2014,one in June in Jakarta and one in November in Beijing, inconjunction with the Developing Country VaccineRegulators Network. The meetings included closed ses-sions for regulators, WHO and DVI, an open session withvaccine manufacturers, and three separate closed sessionswith vaccine manufacturers. Recently, a meeting titled‘WHO technical consultation in partnership with DVI’ orga-nized by the WHO gathered the NRA officials from theseven countries to review the Dengue Vaccine Dossier(28–30 July 2015 in Geneva, Switzerland) to achieve com-mon scientific understanding for review of the registration

dossier of the Sanofi Pasteur vaccine. Participants includedsenior technical decision-makers, as well as eight indepen-dent regulatory experts with experience from differentsystems in Europe, the US, and developing countries.From this meeting, the expectation was that the knowl-edge gained by the participants during the consultationmay be used by each NRA at their discretion and the finaldecision would be individually and independently reachedby each NRA according to their own timeline and as pernational procedures and guidelines.

Further development and refinement of thepoints for consideration

For evidence for decision-making as shown in Table 2,the revised points to be considered for vaccine intro-duction were to standardize case definitions and sever-ity grading for better comparison of efficacy data inclinical trials, and promote consistent use of evaluationtechniques across the country; to conduct sentinel sur-veillance for sero/genotype surveillance; to monitorcase fatality of dengue to justify need for vaccine intro-duction; to collect data needed for the development ofthe vaccination strategy such as serostatus by age; andto strengthen capacity to share information such asthrough quickly accessible electronic information.Some of these points were consistent with recommen-dations from other groups such as the first dengue v2V(vaccine to vaccination) meeting as well as from ASEANDengue Vaccination Advocacy initiative.[20,21] Previousdiscussions on the same topic also insisted on theimportance of the surveillance data to monitor andevaluate intervention programs, thus also highlightingthe need to harmonize surveillance with enhancedlaboratory capacity.[20–23] From the DVI meeting, sev-eral points were emphasized: the importance of linkingdisease surveillance and vaccination registries to moni-tor coverage and vaccine efficacy, pharmacovigilance tomonitor vaccine safety, and working with technical andinternational agencies for supporting vaccine introduc-tions, particularly through activities such as issuingrecommendations for laboratory-based disease surveil-lance in the region with an aim of standardizing testing.With respect to other matters addressed in 2012, therevisions in 2014–15 added emphasis on the need fordata sharing and collaboration among the countries.

For impact modeling, it was recognized that this isa complex undertaking and requires substantial tech-nical expertise in countries applying it. The particularpoints to be considered were to standardize models(terminology, assumptions, etc.); to include guidanceon model selection (deterministic and stochastic) anduse; to promote greater collaboration among

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Table2.

Points

forCo

nsiderationin

preparationforvaccineintrod

uctio

ndevelopedin

2014–2015.

Points

forCo

nsideration(2014–2015)

1.Evidence

fordecision-making

A.Epidem

iologicalsurveillance

-Specify

that

beyond

capacity

tocond

uctepidem

iologicalsurveillance,cou

ntriesshou

ldattempt

to:

Clarify

thecase

defin

ition

used

byeach

coun

tryas

explicitlyas

possible,and

ideally

followWHO/PAH

Orecommendatio

nsforcase

defin

ition

forbetter

comparison

ofclinicaltrialresults;

harm

onizeagegrou

psacross

coun

tries;useageincidenceas

aproxyforserologicalp

revalenceifdesired;

identifyriskgrou

ps;d

etermineprevalence

ofyellow

fevervaccinationif

approp

riate.

-In

additio

n,recommendatio

nsshou

ldalso

includ

e:Optimizinguseof

existin

gdata

(i.e.,incidence

byage,severity,health

serviceutilizatio

ninform

ation);m

apping

risk,andidentifying

riskfactorsto

improvetheinform

ationon

thedisease

burden

andinform

decision

making;

usingliteraturereview

sforbackgrou

ndinform

ation;

usingserologicalp

revalencestud

iesto

complem

entandconfirm

incidenceestim

ates

from

otherdisease-bu

rden

stud

iesor

mathematicalmod

els;review

ingvaccineindicatio

nsto

inform

decision

making.

B.Econom

icstudies

Makethecapacity

forcond

uctin

ghealth

econ

omicassessmentsexplicit,

beyond

thecapabilityto

collect

econ

omicdata,b

ecause

mostcoun

trieswillrequ

irethesefordecision

making.

Specify

that:

-Co

stingstud

iesshou

ldbe

uniform

andgenerate

results

that

areclearandcomparablebetweenstud

iesto

inform

decision

making.

-Stud

iesshou

ldbe

cond

uctedwith

fulltransparency

(particularlywhenfin

ancedby

pharmaceuticalcompanies).

C.Policystudies

Amon

gthespecificstud

ieslisted,

specify

that:

Currentg

uidelines

forvaccine

introd

uctio

nshou

ldbe

review

ed;sustainabilityof

vaccineintrod

uctio

nshou

ldbe

assessed;risk-benefit

assessmentsshou

ldbe

made;po

st-licensurestud

ies

shou

ldbe

cond

uctedforsurveillanceof

AE;evaluationof

vaccineimpact

shou

ldbe

madesoon

aftervaccineintrod

uctio

nto

generate

politicalwillto

sustaintheprog

ram.

D.M

odeling

Impact

mod

elingshou

ldinclud

eestim

ates

ofimpactsfrom

inno

vativeinterventio

nssuch

asWolbachiainfected

malemosqu

itorelease.

2.Impactmodeling

A.Thepotentiala

pplications

ofmodeling

Specify

additio

nala

pplications:

Assessingefficacyandvaccineactio

nfordeng

uevaccinecand

idates

inPh

ase3trials;assessing

optim

alnu

mberof

doses,du

ratio

nof

protectio

n,do

sage

schedu

le;estimatingvaccine

efficacyforsusceptib

ility

toinfection,disease,infectionanddisease,andtransm

ission

tomosqu

itoes;estimatingvaccineeffectiveness,includ

ingindirecteffectsforoveralleffe

ctiveness,

indirect

effectiveness,andtotale

ffectiveness;assessingcoverage

ratesrequ

iredby

dose

toachievetargets.

B.Thecountry’sability

toconductimpactmodeling

Specify

additio

nalcapacities

requ

ired:

Assess

coverage

ratesby

dose;assesstransm

ission

dynamicsin

diffe

rent

scenariosin

thecoun

try.

C.Engagementof

modelingworkwith

decisio

nmakers(additional

category)

Coun

triesconsideringdeng

uevaccineintrod

uctio

nshou

ld:

Survey

decision

makersforneedsandresources;requ

estsugg

estio

nsforspecificvaccinestrategies

tobe

evaluated;

requ

ests

forfeedback

onmod

eled

vaccinestrategies

with

local

concerns

abou

timplem

entatio

n;developgu

idance

onsimpleanalyses

(survival,long

itudinal,analyticresults

from

mod

els)that

cangenerate

similarinform

ationto

mod

els;establish

working

grou

psformod

elinginclud

ingtheearly

adop

tercoun

triesfordeng

uevaccine.

(Con

tinued)

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Table2.

(Con

tinued).

Points

forCo

nsideration(2014–2015)

3.Immunizationsystem

sA.

Thestrategy

forvaccineintroduction

Specify

additio

nalrequirements:

Introd

uctio

nstrategy

mustbe

coun

try-specific;em

phasisshou

ldbe

onprog

rammaticfeasibility;b

erelevant

towhether

vaccineprotects

just

againstdiseaseor

also

infection–

implications

forvaccinationstrategy;g

oodcapacity

forcoun

try-leveld

ecision-makingin

thecoun

tries;working

with

PROVA

Cwou

ldbe

very

useful;strategiesmustbe

realistic

and

sustainablein

thelong

term

.B.

Thebudget

foradengue

vaccine

Itshou

ldspecify

that

thebu

dget

isforthedeng

uecontrolp

rogram

.Itshou

ldadditio

nally

specify

that:

Budg

etshou

ldinclud

evector

controland

bemanaged

inconjun

ctionwith

vector

control;therecouldbe

timelagbefore

vaccines

areavailable(the

timerequ

iredto

pre-qu

alify

avaccine);fun

ding

may

beavailablefrom

externalorganizatio

nsthat

have

supp

orteddeng

uecontrol/vaccines(theymight

beableto

providesomefund

s,as

coun

tryfund

sarelim

ited);

initialbu

dget

requ

irements

forvaccineintrod

uctio

nwillbe

large(e.g.training,

rollou

t).

C.Thecapacity

forimmunizationsurveillance

Specify

additio

nalrequirements:

Capacity

isneeded

toassess

whether

deng

uecasesaredu

eto

missedop

portun

ities

orvaccinefailure,etc.;immun

izationsurveillanceshou

ldno

tbe

isolated

from

deng

uesurveillance;

need

capacity

toconfirm

deng

uecasesto

avoidconfusingotherfebrile

illnesses

with

deng

ue;stand

ardizatio

nforlabo

ratory

confirm

ationandcase

defin

ition

siscritical(go

alsshou

ldbe

setforlabo

ratory

confirm

ation;

surveillancecouldbe

region

allybased,

working

with

coun

tries,to

quicklydetect

impact

(RoleforWHO/PAH

Ogu

idance).

D.The

capacity

formonitorin

gandevaluation

Shou

ldbe

combinedwith

immun

izationsurveillance,andinclud

ethreeareasof

focus:

Disease

surveillance;immun

izationcoverage;vaccine

safety.

E.Thecapacity

ofthecold

chainandlogisticsmanagem

ent

Shou

ldadditio

nally

specify:

Impactof

prod

uctpresentatio

nsize

oncold

chainsystem

shou

ldbe

fully

assessed

(optimalpresentatio

nsize

shou

ldbe

review

edto

minimizewastage

includ

ingfrom

multi-do

sepo

licy);

considerationof

VaccineVialMon

itorisvery

impo

rtant.

F.Thecapacity

oftheinform

ationsystem

Shou

ldadditio

nally

specify:

Immun

izationregistriesarecritically

impo

rtant(electronicregistriesareapriority,with

ability

tolinkwith

patient

recordsso

vaccinationstatus

canbe

assessed

even

yearspo

st-

vaccination).

G.The

capacity

ofthecommunicationsystem

sShou

ldadditio

nally

specify:

Commun

icationisalso

needed

forthoseno

ttargeted

forvaccination;

socialmediacouldbe

very

impo

rtantgiventhepo

tentialrisks

ofnegativepu

blicity;there

shou

ldbe

tracking

ofrespon

sesto

concerns;availabletechno

logies

(e.g.,SM

S)couldbe

utilizedto

increase

awareness;keymessagesinclud

ingvaccinationispartof

anintegrativeapproach

andvaccineesare

not100%

protectedagainstdeng

ue;n

eedto

cond

uctan

assessmentof

commun

ications

capacity

ofthecoun

tryandplan

accordingly;messageson

thevaccineshou

ldbe

integrated

with

messageson

vector

control;workwith

health

prom

otiondepartments;com

mun

icationwillneed

tobe

adjusted

tocircum

stancesof

vaccineavailability.

H.Training

Shou

ldadditio

nally

specify:

Consider

education/training

outsideof

themedicalcommun

ity(e.g.jou

rnalists,p

oliticalleaders);medicaltraining

prog

ramsshou

ldprovideaho

listic

view

ofdeng

uepreventio

nand

control.

4.Demandandfinancing

A.Dem

and

Additio

nalcriteriaforforecastingdemandinclud

es:

Better

defin

ition

ofendemicareasin

deng

ue-end

emiccoun

tries;better

defin

ition

ofdeng

uecaseswith

inendemicareas;clearinform

ationabou

tprod

uctprofile

(e.g.,vaccineto

target

moresevere

deng

uecases–DHF);defined

thresholdof

seroprevalence

towarrant

vaccination;better

defin

edvaccineintrod

uctio

nstrategies

that

consider

geog

raph

iclocatio

nsandage

grou

ps,p

rioritized

bylevelo

fseverityandareasof

greatest

impact.

B.Financing

Addasectionon

sustainablefin

ancing

which

shou

ldspecify:

know

beforehand

thepriceof

thevaccine;assess

thesource

offund

ing(in

ternal

versus

external);consider

optio

nsforprocurem

entmechanism

.Identify

complem

entary

fund

ing

mechanism

s(dengu

e-specificfund

ingmechanism

s,where

otheractorsou

tsidethepu

blicsector

may

have

aninterest).

(Con

tinued)

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modelers; to build more accurate models by countriesbased on local data; to assess funding requirement;and to have external and independent validation ofmodels. The meetings also highlighted the benefit ofmodels in decision-making and exploring the poten-tial impact and the need to better utilize local data byhaving each country run their own models withtrained staff.[20,24] In 2012, the discussion hadbroadly addressed application of modeling and acountry’s adoption of the model. In 2014–2015, thediscussion progressed further to consider what andhow to make the process of model application easierfor the countries to adopt including use of consistentterminology, selection of models that would better fiteach country’s context, using more local data.

For immunization systems, similar points as in 2012were again raised. These included involvement of NITAGand other technical/international agencies for support;having integrated disease surveillance capacity; securingbudget and having logistics capacity in place; and hav-ing a vaccination strategy. Also, the 2014–2015 meetingshighlighted the value of applying lessons learned fromother vaccine introduction and other countries. Thepoints on logistical capacity and infrastructure had alsobeen raised by other groups.[24] More weight wasplaced on the importance of communication in 2014–2015. Communication as a key factor in accelerating newvaccine introduction has been highlighted in previousliterature.[25,26] In addition to the importance of theprogrammatic feasibility, it was recommended to pre-pare more comprehensive communication strategiesand communications training specifically aimed at den-gue vaccines. For example, in the case of roll-out in onlysome parts of a country, the concern was on how tocommunicate the strategic rationale to the public andmedia on introduction-related strategies.

For postlicensure studies, emphasis was given to theimportance of conducting demonstration projects andpostdemonstration surveillance to test the introductionstrategy and assess impact of vaccination. This need tomeasure impact of vaccine introduction and to establishlong-term safety and effectiveness data have also beenmade by other groups,[20,23,24,27,28] as well as by a pre-vious survey conducted by PDVI among policymakers andopinion leaders.[29] In the 2014–2015 meetings, it wassuggested that first-introducer countries should considerschool vaccination coverage to simplify study logistics in anurban setting and consider other means of integratingstudies within the expanded immunization program withthe aim of sustaining and standardizing data collection.Also, the importance of sharing each country’s experiencewith others was highlighted. The work of the DPBs waselaborated in a recent publication by Mahoney.[1]Ta

ble2.

(Con

tinued).

Points

forCo

nsideration(2014–2015)

5.Postlicensure/dem

onstration

projects

Itshou

ldadditio

nally

specify:

-Haveaclear,coherent

plan

onho

wthevaccinewillbe

introd

uced/used(fo

llow/expandPA

HOgu

idance)with

defin

edtarget

popu

latio

nandplan

todeal

with

grou

pswho

areno

ttargeted

forvaccination(because

oflim

itedsupp

ly,etc.).

-Havestrong

epidem

iologicalsystemsto

determ

inevaccineimpact

andidentifysafety

sign

alslong

aftervaccineintrod

uctio

n.-Prepareforsituations

where

vaccineeffectivenessismuchless

than

anticipated:h

aveacommun

ications

plan

prepared.

-Co

nductwellp

lann

edvaccine-effectivenessstud

ies,with

homog

eneous

clinicalandepidem

iologicald

efinition

s(havingsentinel

siteswith

enhanced

surveillance,movingto

PCR

testingforconfirm

ation,

andhaving

pharmacovigilanceplansthat

allow

safety

follow-up,

linkedto

vaccinationrecords).

-Issuelim

itedlicensesto

controlvaccine

introd

uctio

nby

mun

icipalities

orsub-natio

nala

utho

rities.

-Measure

herd

protectio

nsuch

asin

step-wedge

vaccineintrod

uctio

nwhich

includ

eareasof

high

,low

andmod

erateendemicity.

536 J. K. LIM ET AL.

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Expert commentary

Recently, there has been accelerated progress made indengue vaccine development. However, there are stillmany questions unanswered.[30] In line with the originalaim of the PDVI program, DVI has been working with DPBmembers, representatives of the DPB member countriesin Asia and the Americas, as well as other partners toprepare the market and accelerate dengue vaccine intro-duction. However, with known technical challenges anduncertainties in dengue vaccine development, there havebeen various changes in thinking about vaccine introduc-tion strategies. With a vaccine closer to licensure and datafrom phase 3 trials available, the exchange of knowledgeand views on issues facing countries in the planning andintroduction of dengue vaccines resulted in modificationsof the initial set of Points for Consideration so that thecurrent Points for Consideration remain relevant and prac-tical for countries as they potentially undertake denguevaccine introduction. As the capabilities of countries differ,they can refer to these Points for Consideration to makecountry-specific decisions on whether and how to intro-duce dengue vaccine. The work that DVI has completedsince the beginning of 2012 should provide the basis forthe introduction of safe and effective dengue vaccinesthat will help to alleviate the health and economic burdenof dengue suffered by many developing countries of theworld.

Five-year view

There is one dengue vaccine candidate close to licensureand two others about to start phase 3 trials. In the nearfuture, countries in endemic regions will need to makedecisions on vaccine licensure and uptake. Countries thatdecide to introduce the vaccine should be equipped

with thoroughly planned roll-out strategies for a vaccina-tion program considering various aspects of the disease,population, and the vaccine. Vaccine introduction strate-gies will be based on the existing data, from clinicaltrials, mathematical modeling, expert opinion, and pre-vious research outcomes. In addition, as pointed out inthe DPB meetings, countries should share knowledgeand experiences of such vaccine introduction(s). It willbe valuable to continue the dialogue on vaccine intro-duction and strategies among country representatives,with various opinion leaders and experts gathered, suchas at the DPB meetings. Using these meetings as aconsultation forum and a mechanism to exchangeknowledge and ideas to plan for optimal strategies forvaccine roll-out in each country would be valuable forthe particular vaccine being introduced as well as forvaccines introduced in the future.

Acknowledgements

We would like to acknowledge members of the Americas andAsia-Pacific Dengue Prevention Boards for their contributionto develop the Points for Consideration. We also thank thepartners of the DVI consortium, DVI NRA group, Dr. LilianaChocarro and participants of the DVI DPB meetings for theirinput.

Financial & competing interests disclosure

This work was supported by grants from the Bill and MelindaGates Foundation to the Dengue Vaccine Initiative. Also, thiswork was supported by an unrestricted grant from SanofiPasteur. The authors have no other relevant affiliations orfinancial involvement with any organization or entity with afinancial interest in or financial conflict with the subject mat-ter or materials discussed in the manuscript apart from thosedisclosed.

Key issues

● After more than a half a century’s effort, the first vaccine candidate is now very close to licensure. There are still some unansweredquestions about this most advanced candidate, which has undergone phase 2b and 3 trials.

● The Dengue Vaccine Initiative (DVI), and its predecessor the Pediatric Dengue Vaccine Initiative, has been working to prepare themarket and accelerate dengue vaccine introduction.

● DVI has gathered technical experts, country representatives, vaccine developers, modelers, etc., to discuss the key capabilities thatcountries would need for effective vaccine introduction. Discussions focused on the data need for decision-making, modeling to betterforecast vaccine impact, gaps in current immunization systems, and financing strategies.

● As dengue epidemiology and existing public health capacity differ by country, any vaccine introduction plans should be country-specific.

● To facilitate comparisons among countries, standardized approaches to conducting controlled introductions (e.g., use of the samedefinition, criteria, etc.) would be ideal.

● DPB meeting participants agreed that controlled roll-out of a vaccine should include post-licensure studies to measure vaccineeffectiveness and impact.

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