Citation for this paper:
Gottlieb, S.L., Deal, C.D., Giersing, B., Rees, H., Boland, G., Johnston, C., …
Broute, N. (2016). The global roadmap for advancing development of vaccines
against sexually transmitted infections: Update and next steps. Vaccine, 34,
2939-2947.
http://dx.doi.org/10.1016/j.vaccine.2016.03.111
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The global roadmap for advancing development of vaccines against sexually
transmitted infections: Update and next steps
Sami L. Gottlieb, Carolyn D. Deal, Birgitte Giersing, Helen Rees, Gail Boland,
Christine Johnston, Peter Timms, Scott D. Gray-Owen, Ann E. Jerse, Caroline E.
Cameron, Vasee S. Moorthy, James Kiarie, Nathalie Broutet
2016
© 2016 World Health Organization; licensee Elsevier Ltd. This is an open access
article under the CC BY license (
http://creativecommons.org/licenses/by/3.0/
).
This article was originally published at:
http://dx.doi.org/10.1016/j.vaccine.2016.03.111
Vaccine
jo u rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e
The
global
roadmap
for
advancing
development
of
vaccines
against
sexually
transmitted
infections:
Update
and
next
steps
Sami
L.
Gottlieb
a,∗,
Carolyn
D.
Deal
b,
Birgitte
Giersing
a,
Helen
Rees
c,
Gail
Bolan
d,
Christine
Johnston
e,
Peter
Timms
f,
Scott
D.
Gray-Owen
g,
Ann
E.
Jerse
h,
Caroline
E.
Cameron
i,
Vasee
S.
Moorthy
a,
James
Kiarie
a,
Nathalie
Broutet
aaWorldHealthOrganization,Geneva,Switzerland
bNationalInstituteofAllergyandInfectiousDiseases,Bethesda,MD,USA
cWitsReproductiveHealthandHIVInstitute,UniversityoftheWitswatersrand,Johannesburg,SouthAfrica dCentersforDiseaseControlandPrevention,Atlanta,GA,USA
eUniversityofWashington,Seattle,WA,USA
fUniversityofSunshineCoast,QueenslandAustraliaandInstituteofHealthandBiomedicalInnovation,QueenslandUniversityofTechnology, Brisbane,Australia
gUniversityofToronto,Toronto,ON,Canada hUniformedServicesUniversity,Bethesda,MD,USA iUniversityofVictoria,Victoria,BC,Canada
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Availableonline19April2016 Keywords:
Sexuallytransmittedinfections Vaccines
STIvaccinedevelopment Roadmap
a
b
s
t
r
a
c
t
In2014,theWorldHealthOrganization,theUSNationalInstitutesofHealth,andglobaltechnical part-nerspublishedacomprehensiveroadmapfordevelopmentofnewvaccinesagainstsexuallytransmitted infections(STIs).Sinceitspublication,progresshasbeenmadeinseveralroadmapactivities:obtaining betterepidemiologicdatatoestablishthepublichealthrationaleforSTIvaccines,modelingthetheoretical impactoffuturevaccines,advancingbasicscienceresearch,definingpreferredproductcharacteristicsfor first-generationvaccines,andencouraginginvestmentinSTIvaccinedevelopment.Thisarticlereviews theseoverarchingroadmapactivities,providesupdatesonresearchanddevelopmentofindividual vac-cinesagainstherpessimplexvirus,Chlamydiatrachomatis,Neisseriagonorrhoeae,andTreponemapallidum, anddiscussesimportantnextstepstoadvancetheglobalroadmapforSTIvaccinedevelopment.
©2016WorldHealthOrganization;licenseeElsevierLtd.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/3.0/).
1. Introduction
Vaccines againstsexually transmitted infections (STIs) are a major priority for sustainable global STI control. Development of new STI vaccines is critical because of the large number of infectionsworldwide,theresultingadversesexual,reproductive and maternal-child health outcomes,and important limitations ofexistingSTIinterventions.Safeandhighlyefficaciousvaccines againsthumanpapillomavirus(HPV)andhepatitis Bvirushave beenmajoradvancesinSTIpreventionandprovideinspirationfor developmentofnewSTIvaccines.
The World Health Organization (WHO) estimates that 357 millionnew casesof curable STIsoccurredin 2012worldwide, includingChlamydiatrachomatis(chlamydia),Neisseriagonorrhoeae
∗ Correspondingauthorat:DepartmentofReproductiveHealthandResearch, WHO,AvenueAppia20,CH-1211Geneva27,Switzerland.Tel.:+41227913424.
E-mailaddress:gottliebs@who.int(S.L.Gottlieb).
(gonorrhea),Treponemapallidum(syphilis),andTrichomonas vagi-nalis (trichomoniasis) infections [1]. STI numbers were high across all world regions (Fig. 1). In addition, prevalent her-pes simplex virus type 2 (HSV-2) infection, the main cause of genital herpes, affected an estimated 417 million people globally in 2012 (Fig. 2) [2], and more than 100million addi-tional people were estimated to have genital infection with HSV-1[3].
STIs can result in a number of adverse outcomes. Mother-to-childtransmissionofsyphilisleadstoover300,000fetaland neonataldeathsperyear[4].HPVcausesover500,000casesof cer-vicalcancerannually[5].Chlamydiaandgonorrheaareimportant causesofpelvicinflammatorydisease(PID)inwomen,whichcan leadtoinfertility,ectopicpregnancyandchronicpelvicpain[6,7]. Inaddition,severalSTIsleadtoanincreasedriskofacquiringor transmittingHIV.HSV-2infectionincreasestheriskofHIV acqui-sitionbythree-fold[8].Nottobeforgotten,thegenitalsymptoms andpsychosocialconsequencesofSTIshaveimportanteffectson qualityoflife.
http://dx.doi.org/10.1016/j.vaccine.2016.03.111
2940 S.L.Gottliebetal./Vaccine34(2016)2939–2947
WHO African Region
WHO Region of the Americas WHO South-East Asia Region WHO European Region
WHO Eastern Mediterranean Region
WHO Western Pacific Region
64 million 142 million 18 million 63 million 31 million 39 million
Fig.1.Globalandregionalestimatesofthenumberofnewcasesof4curableSTIs(chlamydia,gonorrhea,syphilis,andtrichomoniasis)among15-49year-oldsin2012. Globaltotal=357millionincidentinfections[1].
Fig.2.GlobalandregionalestimatesofthenumberofprevalentcasesofHSV-2infectionamong15–49year-oldsin2012.Globaltotal=417millionprevalentinfections[2].
CurrentSTI controlischallengedbyseveralfactors[9].First, althoughcondomsareanimportantSTIpreventiontool,therehave beenlimitstoprogressmadewithcondomsasthemainprimary prevention measure. Second, most STIs are asymptomatic, and availabilityofaffordable,feasibleandrapidtestsislackinginmany settings.Especiallyinlower-incomecountries,mostinfectionsare notdiagnosed.Chlamydiascreeningprogramsforyoungwomen have been difficult to bring to scale in high-income countries andbythemselves,withoutastrongfocusonpartnertreatment, have notresulted in clearreductions in sexualtransmission of chlamydiainfections[10].Third,thegrowingthreatof antimicro-bialresistance,withincreasingreportsofcephalosporin-resistant gonorrhea,createsanurgentneedfornewpreventiontools[11]. Supplychain shortages ofantibiotics, e.g.,benzathinepenicillin
for syphilis, are also a major concern. Finally, STIs are often stigmatizingandhavereceivedlittlepublicpolicyattention. With-outasimple,clearlyeffectiveintervention,ithasbeendifficultto garnersupport[9,12].Thus,whileeffortstoscaleupexisting inter-ventionscontinue,thesechallengeshighlighttheneedforongoing worktowardSTIvaccinedevelopment.
2. STIvaccineroadmap
In2013,WHOandtheNationalInstitutesofHealth(NIH) orga-nized a technical consultation to evaluate how to advance STI vaccinedevelopment.Theconsultationresultedinaspecialissue of the journal Vaccine in 2014, which included articles onthe prospects for newvaccines against HSV, chlamydia, gonorrhea,
1.ObtainbetterepidemiologicdataonSTIburden 6.Definepreferredproductcharacteristicsfor1stgenerationvaccines 2.ImproveunderstandingofSTInaturalhistoryandsequelae 7.Expediteclinicaldevelopmentandevaluation
3.Modelthetheoreticalimpactandcost-effectivenessofSTIvaccines 8.Planforvaccineintroductioninadvance
4.AdvancebasicscienceresearchforSTIvaccines 9.EncourageinvestmentinSTIvaccinedevelopment
5.Conductbasicandtranslationalstudiesinhumanclinicalsettingsassoonaspossible
syphilis,andtrichomoniasis[13].Thespecialissueconcludedwith
aproposedglobalroadmapforSTIvaccinedevelopment[14].The roadmapwasdevelopedbyconsensus,basedondiscussionsatthe technicalconsultation,andoutlinescriticalnextstepsfrom pre-vaccinedevelopmentthroughvaccineintroduction.
Vaccine developmentisa long,expensiveand riskyprocess, whichprogressesalong adefineddevelopmentpathway[15].In thediscoverystage,basicscienceresearchaimstounderstandthe diseaseandprotectiveimmunemechanismsinordertoselecta candidatevaccine.Typically,preclinicalstudiesinanimalmodels evaluatethesecandidates.Clinicaldevelopmentinvolveshuman studies.SmallPhaseIstudiesevaluatesafety,whileslightlylarger Phase IItrials further characterize safety, immunogenicity, for-mulationsand doses.PhaseIIIstudiesevaluatevaccine efficacy andsafetyinlargerandomized,placebo-controlledtrials. Success-fulvaccinesthenneedregulatoryapproval.Ateachstage,several “go”/“nogo”decisionsdeterminewhethertheprocessmoves for-ward,particularlyinearlydevelopmentasacandidateisoptimized beforecommitmentto expensivePhaseIIItrials. “Push” forces, suchasadvancesintechnologyoraninfluxoffunding,and“pull” forces,suchasaclearlydefineddiseaseburdenorstrongmarket forthevaccine,canhelpacceleratevaccinedevelopmentthrough thestages.
TheSTIvaccineroadmapoutlines9priorityactionareas,with specificactionsteps,thatcangeneratepushandpullforcesand cat-alyzestepsinbetween,toadvancevaccinedevelopment(Table1). This article presents an overview of key overarching activities undertakentodatetoadvancetheSTIvaccineroadmapinthe fol-lowingareas:obtainingbetterepidemiologicdata,modelingthe impactofSTIvaccines,advancingbasicscienceresearch,defining preferredproductcharacteristics,andencouraginginvestmentin STIvaccinedevelopment.Wethenprovideupdateson develop-mentofindividualSTIvaccines.
3. OverarchingadvancesinimplementingtheSTIvaccine roadmap
3.1. ObtainingbetterepidemiologicdataonSTIburden
Oneofthekeyactionitemsinthisareaoftheroadmapwasto updateglobalandregionalestimatesofSTIburden.In2015,WHO updatedestimatesoftheglobalprevalenceandincidenceofHSV-2 infection[2],andreleasedthefirst-everglobalestimatesofHSV-1 infection[3].Anestimated417millionpeopleaged15–49years hadHSV-2infection(11.3%prevalence)in2012[2].HSV-1 infec-tionaffectedanestimated3.7billionpeopleaged0–49years(67% prevalence),ofwhomanestimated140millionpeoplehad HSV-1genitalinfection[3].Thus,morethan500millionpeopleaged 15–49yearshadgenitalinfectionwitheitherHSV-1orHSV-2[2,3]. Thesefiguresarecurrentlybeingusedtogenerateestimatesofthe burdenofneonatalherpesinfections,expectedin2016.
HSV-2infectionwasalsoaddedtoconditionsevaluatedinthe GlobalBurdenofDisease(GBD)Study2013,whichestimatedthat HSV-2 infection resulted in 311,600 years lived withdisability (YLD)in 2013fromgenital ulcerdiseasealone [16].TheseYLD estimates do not include disability due toneonatal herpesnor HSV-associatedHIVacquisition,which arethemostdevastating consequencesof infection.The GBDstudyhasongoing updates,
whichwillcontinuetorefinethemethodologyforevaluatingYLD associatedwithHSV,includingconsiderationofaddingHSVasa riskfactorforHIV.
Updated curable STI estimates were also publishedin 2015 [1].In2012,therewereanestimated131millionnewchlamydia infections,78millionnewgonorrheainfections,5.6millionnew syphilisinfectionsand143millionnewtrichomoniasisinfections [1].TheGBD2013studydemonstratedthatalthoughsyphilishad thefewestnumberofcases,itsassociatedfetalandneonatal com-plicationsmeantsyphilishadthehighestdisability-adjustedlife yearslostofallthecurableSTIs[17].Inmanyregions,and espe-ciallyformen,theseSTIestimateswereconstrainedbyapaucity ofpublishedprevalencedata.Followingaconsultationmeetingin 2015,WHOispursuingstrategiestostrengthencountry-levelSTI surveillanceandimprovethemethodologyforfutureestimates. ImprovedglobaldataontheburdenofPIDandinfertilityrelatedto chlamydiaandgonorrheawillalsobeimportant.
AsdenovodedicatedSTIburdenstudiesmaybetoo resource-intensive and not realistic in many settings, another roadmap recommendationwastopartnerwithresearchsitestoleverage existing but non-published STIdata. One suchprojectthat has emergedfromthesediscussionsisSTIMA,anSTIindividual partic-ipantdatameta-analysisusingcombineddatafrom18prospective HIVpreventionstudies,whichwereinitiallycombinedtolookat theeffectofhormonalcontraceptiononHIVacquisition[18].These datarepresentover 37,000womeninsub-Saharan Africa,more than95%ofwhomhavedatawithwhichSTIprevalenceorincidence canbeassessed.Inthefuture,inadditiontonewerHIV preven-tiontrials,itwillbeimportanttoconsiderevaluatingSTIdatafrom HPVvaccine,circumcision,andcontraceptiontrials.Itwillalsobe importanttocontinuetoseekopportunitiestoaddSTIvariables tosurveillancestudiesandclinicalandpreventiontrials,especially fromtheoutset.
3.2. ModelingthetheoreticalimpactofSTIvaccines
AnHSVvaccinemodelingmeetingwasheldatWHOinMarch 2015toreviewexistingmodelsandidentifymodelingneedsrelated toHSVinfection,costsandthetheoreticalimpactofanHSV vac-cine.SeveralexistingmodelsshowedthatevenanimperfectHSV vaccinecouldbebeneficial[19–21].However,thegroupoutlined several newmodeling needscritical to advancingHSV vaccine developmentanddecision-makinginthefuture,suchasinclusion ofHSV-associatedHIVincidenceandneonatalherpesasmodel out-comesandincorporationofHSV-1infection,bothasanoutcome andasapotentialmodifieroftheimpactonHSV-2.Thegroupalso recommendedmodelingindifferentepidemiologicandeconomic settings,andinclusionofcost-effectivenessanalyses.Inorderto conductthesemodels,betterprimarydatafromlow-and middle-incomecountries(LMICs)onneonatalherpesandonthecostsof HSVwillbecrucial.TheplannedChildHealthandMortality Pre-ventionSurveillance(CHAMPS)network[22],whichwillexplore thecausesofneonataldeathsindevelopingcountries,mayallow collectionofmuchneededdataonfatalneonatalHSVinfections.
Newchlamydiavaccinemodelingeffortsin2015includework suggesting that a successful chlamydia vaccine could be cost-effective [23]. Although there are many unknowns related to chlamydialvaccinedevelopment,thesekindsofexerciseslaythe
2942 S.L.Gottliebetal./Vaccine34(2016)2939–2947
Fig.3. Elementsofthecomprehensivevaccinebusinesscase.PPCs=preferredproductcharacteristics.
frameworkforthinkingthroughpertinentassumptionsandmodel structure,andcanbeupdatedasvaccinedevelopmentadvances. 3.3. Advancingbasicscienceresearch
TheUS NationalInstitute of Allergy and Infectious Diseases (NIAID),partoftheNIH,hasheldseveralworkshopsfocusedon advancingbasicscienceforSTIvaccinedevelopment.Thereport of a workshop for HSV vaccine development waspublished in thespecialissueofthejournalVaccinein2014[24].Workshops werealsoheldtofocusongapsandchallengesforthe develop-mentofchlamydiaandgonorrheavaccines.InMay2015,chlamydia researchersfromaroundtheworldgatheredtodiscussthestatus ofchlamydiavaccinedevelopment,gapsincurrentknowledgeof immuneresponsesandincorrelatesofprotectiveimmunity,the potentialbenefitsofaneffectivechlamydiavaccine,andissues per-tainingtoclinicaltestingofvaccinecandidates.Asimilarmeeting washeldinJune2015todiscussavaccinetopreventgonococcal infection.Reportsfrombothworkshopswillbereleasedin2016.
Oneofthegoalsoftheseworkshopswastoidentifypotential reagents,immunogens,andassaysthat,ifstandardizedandmade availabletoresearchers,mightacceleratemovingvaccine candi-datesfromanimalstudiesintoclinicalevaluation.Tofacilitatethis process,NIAID offerstargeted product developmentsupportto assistinidentifyingandfillingcriticalgapsintheproduct devel-opmentpipeline.
3.4. Definingpreferredproductcharacteristics
Preferred product characteristics (PPCs) reflect formal WHO guidanceonthedesiredparametersofavaccinethatwouldmeet prioritypublichealthgoals,especiallyforLMICs[25].APPC doc-umentdescribescharacteristicssuchasvaccineindications,target groups,possibleimmunizationstrategies,anddesiredclinicaltrial datarelatedtosafetyandefficacy,e.g.,whethertheendpointis pre-ventionofmorbidityorinfection,ortheefficacyrequirementsto achieveaminimumpublichealtheffect[26].PPCsareintendedto provideearlyguidancetoanyentityintendingtoeventuallyseek WHOvaccineprequalificationand policyrecommendations,and maybedistinguishedfromindustry-generatedtargetproduct pro-filesinthattheyaretailoredspecificallytotheneedsofLMICs.PPCs arederivedthroughastakeholderconsultationprocessthat estab-lishesasharedglobalvisionandaregeneratedforvaccinesthat WHOconsidersapublichealthpriority.Thus,theyengage regula-torsandpolicy-makersearlyonandcancatalyzeindustrysupport andshapetargetproductprofilesusedbyindustryandbysome fundingentities.
The ProductDevelopment for Vaccines AdvisoryCommittee (PD-VAC)providesstrategicadvicetoWHOrelatedtovaccinesin earlyclinicaldevelopment,andmakesrecommendationsrelated todeveloping PPCsfor a particularvaccine. HSVvaccines were
reviewedatthe2015PD-VACmeeting(backgroundpaperby John-ston et al. [27]). Because of the global immunization focus on preventingdeathsinchildrenunder5years,PD-VACrecommended studiestoobtainbetterdataonneonatalherpesinLMICs,in par-ticularthroughtheCHAMPSevaluation.BecauseHSV-2infectionis associatedwithanincreasedriskofHIV infection,withan esti-mated population attributable risk percentage of 48% in some populations[28],thecommitteeencouragedmodelingstudiesto evaluatethepotentialfor HSVvaccines toreduceHIVinfection rates. Finally, PD-VAC supported the development of a robust investmentcase,includingassessmentofpotentialvaccineimpact onabroadarrayofHSV-2andHSV-1outcomes,inordertocatalyze furtherHSVvaccineresearchanddevelopment.
3.5. EncouraginginvestmentinSTIvaccinedevelopment
InlinewiththeSTIvaccineroadmapandPD-VAC recommenda-tions,WHOaimstogenerateacomprehensivebusinesscasefor HSVvaccinedevelopmenttooutlinethepublichealthrationale forthevaccine.Thebusinesscase firstdemonstrates thepublic healthneedfor thevaccineinterms ofthediseaseburden and costs(Fig.3).Thishelps determinethemarketfor thevaccine, withinthecontextofcompetinginterventions,andallows mod-elingofpotentialvaccineimpactandcost-effectiveness.Outlining diseaseburdenepidemiologyand modelingvaccineimpactalso facilitatedefining preferredproduct characteristics.ThesePPCs, along withbasicscienceand technology, determinetheprecise vaccinedevelopmentpathwayandcosts.Thebalanceofthe pro-jectedmarketdemandandvaccineimpactwiththeprojectedcosts ofvaccinedevelopmentdeterminesthepotentialreturnon invest-ment.Onceavailable,thebusinesscasedocumentwillhelpinform decision-makingand rationalizeinvestmentby varied stakehol-ders,includingdonors,vaccinedevelopersandmanufacturers,and policymakers.To date,a detailed workplan and budgetfor an HSVvaccinebusinesscasehasbeendeveloped.Businesscasesfor chlamydia,followedbyotherSTIvaccines,willalsobeinstructive asdevelopmentofthesevaccinesadvances.
RaisingawarenessaboutSTIvaccinedevelopmentisalsocritical for encouraginginvestment. Since developmentof theSTI vac-cineroadmap,theglobalintroductionofHPVvaccine,includingin LMICs,hasproducedwidespreadrecognitionthatSTIvaccinescan besuccessfullyintroduced.TheglobalneedfordevelopmentofSTI vaccineshasalsobeenhighlightedinanumberofacademicforums, suchastheGlobalVaccineandImmunisationResearchForumand theWorldSTIandHIVCongress.
4. ProgressinresearchanddevelopmentofindividualSTI vaccines
ThecurrentstatusofthedevelopmentpathwayforSTIvaccines isshowninFig.4.Vaccinedevelopmenteffortsarefurthestalongfor
Fig.4. CurrentstatusofthedevelopmentpathwayofSTIvaccines.
HSV,forwhichseveralvaccinecandidatesareinPhaseIandIItrials. Progresshasbeenmadeinthepreclinicaldevelopmentof chlamy-diavaccinecandidates,withthefirstPhaseIclinicaltrialsexpected tostartin2016.Vaccinedevelopmentisnotasadvancedalongthe developmentpathwayforgonorrheaandsyphilis,butcandidates areemergingthatcouldbedevelopedoverthenextseveralyears. Updatesontheprogressinresearchanddevelopmentforthesefour vaccinesfollow.Thepathtovaccinedevelopmentfor trichomonia-sisistheleastunderstood,withmorebasicscienceresearchneeded, aswellasbetterepidemiologicandnaturalhistorydata.
4.1. Herpessimplexvirus
TheSTI vaccine roadmap catalyzedthe HSVvaccine field in severalimportantways.Inadditiontothenewglobalestimates ofHSV-1andHSV-2infectiondemonstratingthehighburdenof HSVinfectionworldwide,theroadmapalsostimulateddiscussion aboutthePPCsofanHSVvaccine.Aprophylacticvaccineto pre-ventgenitalHSVinfection,whichwouldbeeffectiveinbothHSV-1 seropositiveandseronegativepersonsandcouldbegiveneitheras partoftheadolescentorchildhoodplatform,wouldbeideal.The mostrecentprophylacticPhaseIIIHSVvaccinetrialtestedasubunit glycoproteinD2vaccinetopreventsymptomaticgenitalherpes dis-easein8323NorthAmericanHSV-1/HSV-2seronegativewomen [29].Thevaccinedemonstratedefficacyofonly20%againstgenital herpesdisease,whichdidnotjustifycontinueddevelopmentofthis candidate.However,severalimportantfindingsemergedfromthis landmarktrial.Surprisingly,theoverallattackrateforsymptomatic genitalHSVdiseasewasonly1.1%[29],suggestingthatfuturetrials shouldconsidereitheranalternativeendpoint,suchasHSV infec-tion,orbeconductedinindividualsatgreaterriskofgenitalHSV disease.Furthermore,ofthe183womeninthetrialwhobecame infectedwithHSV,only62(34%)hadsymptomaticorsuspected genitaldiseaseand121(66%)acquiredHSV-1,demonstratingthe importanceofbothasymptomaticinfectionandtheemergingrole ofgenitalHSV-1[30].Finally,higherantibodytiterstogD-2were associatedwithincreasedvaccineefficacyagainstHSV-1infection anddisease,suggestingthefirstimmunecorrelateofprotection againstHSV[31].Theresultsfromthistrialwillbeinstrumental indefining PPCsanddesigning futureprophylacticHSVvaccine trials.
DespitethedisappointingefficacyresultsofthePhaseIIItrial, theHSVvaccinefieldremainsveryactive.Fivevaccinecandidates haveenteredPhaseI/IItestingoverthepasttwoyears,and numer-ousothercandidatesareindevelopment.Thesevaccinecandidates arereviewedinmoredetailintheHSVvaccinedevelopmentbrief byJohnstonetal.[27].Fourvaccinecandidatesbeingevaluated inearlyclinicalstudiesusenovelepitope/adjuvantcombinations, andonecandidateinPhaseIstudies,HSV529,isalive, replication-defectiveHSV-2vaccinecandidatewithdeletionsinUL5andUL29 [32]. Most of the vaccines in clinicaltrials are currentlybeing testedinpersonswithHSV-2infectiontoreducegenitalherpes recurrencesandshedding(“therapeuticvaccination”)ratherthan
topreventinfectionamongHSVseronegativeindividuals.These earlyphasestudiesoftherapeuticHSVvaccinesareusinga reduc-tioninthefrequencyofgenitalHSVsheddingastheprimaryclinical endpoint,ratherthantimetofirstgenitalherpesrecurrence,which hasbeenusedinpreviousstudies[33].BecauseHSVsheddingisin thecausalpathwayforHSVrecurrences,itisanexcellentbiomarker forHSVdiseaseseverity[34].
Promising preliminary resultsfrom the Phase II trialof the GEN-003therapeuticvaccine,aproteinsubunitvaccinewithgD2 and ICP4and MatrixM2adjuvant,have shownanapproximate 50%declineinthegenitalHSVsheddingrate,withsimilarinterim resultsseeninadose-findingPhaseIItrial[35].APhaseIIstudyof theHerpVvaccine,a32-peptidevaccinelinkedtoheatshock pro-teinandQS-21adjuvant,showeda15%declineinHSVshedding frequency.ResultsfromtwoDNAvaccinescurrentlyinPhaseII tri-alsareeagerlyawaited[36,37].Otheradvancesinthefieldinclude theincreasingnumberoffull-lengthHSVgenomeswhichhavebeen sequencedfromaroundtheworld[38–40].Sequencingdatahave revealedthatvaccinecandidateglycoproteinDishighlyconserved betweenHSV-1andHSV-2[41].DatashowingthatgDandgB stim-ulatethedominantneutralizingantibodyresponsetoHSV,aswell asgreaterunderstandingoftheimportanceoftype-specific neu-tralizingantibodyresponsestoHSVinfectionwillguidevaccine development[42].Inaddition,recentlyidentifiedtissueresident memoryCD8+T-cellsmaybeimportanttostimulate,forboth pro-phylacticandtherapeuticvaccination[43].Therecentmomentum intheHSVvaccinefieldlaysthegroundworkfornovelapproaches toHSVvaccinedesignandprovideshopethateffectiveHSV vac-cinesmaybedevelopedinthenearfuture.
4.2. C.trachomatis
The prospects for a C. trachomatis vaccine are increasingly promising,primarilybecausethelast3yearshasseentherapid developmentofnewtoolsforChlamydiaresearchthatwill acceler-atevaccinedevelopment.Oneofthemajordevelopmentshasbeen thelong-awaitedtechnologytogeneticallymanipulateChlamydia [44].Bypayingcarefulattentiontodetail,itispossibletocureC. tra-chomatisofitsnativeplasmidandthentoengineertheplasmidto containanEscherichiacolioriginandsubsequentlyre-introducethe plasmidwithatestableforeigngene.Animportantcomplementing strategyhasbeentheproductionofmutantlibraries.Atthistime, theselibrariesarenotusuallyisogenic(i.e.,onlycontainchanges inasinglegene).Nevertheless,becauseitisrelativelyinexpensive tosequenceclonedisolatesfromsuchlibraries,andthesecloned mutantstrainscanbetestedbothinvitroandinvivo,severalgroups arenowmakinguseofthistechnologytoidentifyandcharacterize novelvirulencegenes[45–48].Onelaboratoryhastestedeachofthe openreadingframesofthechlamydialplasmidandhasidentified keyrolesforpgp3andpgp4[45,49].Anotherhasusedthis strat-egytoanalyzeanincreasingnumberofkeychlamydialproteins [46–48].Together,theseapproachesarefacilitatingidentification andvalidationofnovelvaccinetargets.
2944 S.L.Gottliebetal./Vaccine34(2016)2939–2947
WhiletheChlamydiamuridarummousemodelhaslongbeen used by chlamydiologists for both basic science and vaccine development,it is widelyacknowledged tohave several short-comings.Workhasthereforecontinuedtoutilizethenon-human primate model and this has enabled testing of an attenuated plasmid-free chlamydial strainas a potential trachomavaccine [50].Overalltheresultsarequitepromising,withtheplasmid-free strainofC.trachomatisproducingverymildeyeinfectionsand pro-vidingsignificantprotectionagainstwildtypechallenge.Thereisa wordofwarningassubtledifferencesintheocularversusgenital tractsitesmayresultinunexpectedlydifferentoutcomes[51].A novelmini-pigmodelhasallowedevaluationofamulti-subunit majoroutermembrane protein(MOMP)-derived vaccine candi-dateagainstsexuallytransmittedchlamydialinfections,whichwas highlyimmunogenic and offeredpromising levelsofprotection againstvaginal C.trachomatisinfectioninimmunizedpigs [52]. Afirst-generationvaccinecandidatebasedonthistechnologyis scheduledtoenterphaseIclinicaltrialsin2016[53].
Akeyaspectofanyvaccineworkistodevelopcorrelatesof pro-tectionandtobetterunderstandthemechanismsofimmunity.A keypublicationin2015showedthatbyutilizingnovel adjuvant-antigenstrategies(charge-switchingsyntheticadjuvantparticles), itwaspossible,usingthemousemodel,tonot onlystimulate a strongCD4response tochlamydial infection,but alsoto direct ittothegenitalmucosawhere itis required[54].For a genital C.trachomatisvaccinetobeeffective,itwilllikely needtoelicit tissue-residentTcells.WhilethechlamydialMOMPhaslongbeen thefocus of vaccine development,several new candidate anti-gens(e.g.,polymorphicmembraneproteins[PMPs])areemerging andareshowinggreatpromise,inbothmouseandprimate mod-els.Combinedwiththeliveattenuatedvaccinestrategy,plusan expandinglistofnoveladjuvants,thereisgreatpromiseformore vaccinecandidatestobedeveloped.Overall,newtoolsandnew discoveriescertainlybringnewhopetoC.trachomatisSTIvaccine development,anditislikelythatseveralcandidatevaccineswill enterPhaseIclinicaltrialsinthenextfewyears.
4.3. N.gonorrhoeae
Despitetheintenseinnateinflammatoryresponsethatisthe hallmarkofN.gonorrhoeae,thereisnonaturallyacquired immu-nitytothebacteria,makingit difficulttopredictwhich type(s) of response might be protective. Moreover, N. gonorrhoeae is exquisitelyadapted to lifein humans, and this hostrestriction hashamperedeffortstomodelinfectionordisease,whichwould provideinsightastohowthesebacteriapersistwithintheinfected mucosa.Whilethesechallengeshavehamperedprogresson vac-cine development, the urgency associated with emergence of multidrug-resistantgonococcalstrainshasdovetailedwithrecent advancesingenomicdiversity,modelinginfectionandour under-standingofimmunitytore-invigoratethefield.
Perhapsthesinglegreatesthurdleinthedevelopmentofa gono-coccalvaccinestemsfromthehostrestrictionofthesebacteria, whichmakesitdifficulttoestablishgonococcalinfectionin labora-toryanimals.Demonstrationthatestradiol-treatedmicebecome colonized with N. gonorrhoeae after vaginal inoculation was a majoradvanceinthisregard,providingamodelinwhich candi-datevaccinescanbetested[55].Studiesusingthismodel have recentlyprovidednewinsightintotheimmuneresponseto infec-tion.Specifically,normal infectionelicitsaninflammatory Th17 response that precludes developmentof adaptive immunity; if cytokineorotheradjuvantsareusedtoskewthistoaTh1-based response,micebecomeimmunetorepeatinfection[56,57].The presenceofhostrestrictionsalsomakesitdifficulttouseanimal modelsto appreciate thecontribution of virulence factors that arespecificforhumans.Ongoingworkto‘humanize’mice,such
asby generationof transgenicanimalsexpressinghuman CEA-CAMreceptorstowhichgonococciadhere,humantransferrinand lactoferrinthattheyuseforiron,andhuman-derivedcomplement regulatory proteins that gonococci use to evade complement-mediated killing, hasprovided models of uncomplicated lower genitaltractinfectionandpelvicinflammatorydiseasethatmore closely reflect gonococcal infection within the human genital mucosa.Theseprovideanexcitingplatformtofocusvaccine devel-opmenteffortsontargetsthatprovideessentialfunctions,andto test thepotentialimpactof antigen-specific immuneresponses againstthesetargets.
Whilemoresophisticatedmousemodelsallowsystematic eval-uationofvaccineantigens,adjuvantsandimmunizationroutes,and enableasearchforcorrelatesofprotection,itisclearthatsome aspectsofimmunitymaydifferbetweenmiceandhumans.This hasmotivatedeffortstore-establishclinicalcohortstostudythe naturalhistoryofgonococcalinfection[58],providesampleswith whichtounderstandgenome[59]andtranscriptome[60]diversity amonggonococcalisolates,andtoexploit‘omics’-levelapproaches todiscriminatebetweenprotectiveandpathogenichostresponses. Thesestudieswillundoubtedlyprovidearicherunderstandingof thegonococcal lifestyleandhelpvalidatevariousaspectsofthe mouse-basedstudies.Providingacriticallinkbetweenthesetwo approacheshasbeentherecentre-establishmentof experimen-talhumanmaleurethrainfectionstudiesattheUniversityofNorth CarolinaatChapelHill[61].Whilerestrictedinitscapacitytoassess largenumbersofvariables,theimportanceofthismodelfor con-firmingthecontributionof virulencefactorsorestablishingthe efficacyofcandidatevaccinescannotbeoverstated.
Theemergenceofmultidrug-resistantN.gonorrhoeaehasledto aglobalawarenessoftheurgentthreatpresentedbythispathogen. Thishas promptedgenome sequencing-based efforts to under-standdrugresistance,whichprovidesapopulation-levelviewof gonococcal geneticdiversitythat allowsthevariability of puta-tivevaccinetargetstobeappreciated.Thisnewunderstandingis emerginginparallelwiththesophisticationofpreclinicalmouse, experimentalhumanandpopulation-basedstudiesofgonococcal infection.Momentumineachoftheseendeavorshasledgonococcal investigatorstoaimtointegratethevariedeffortsbeingundertaken todevelopnewvaccines,andtodevelopapipelineofcandidates toexpeditethepathinto clinicaltrialsand supportthegoalof deliveringaneffectivegonococcalvaccine.
4.4. T.pallidum
Althoughsomeprogresshasbeenmadeinreducingthe num-berofsyphilisinfectionsglobally[1],syphilisremainsanimportant causeoffetalandneonatalmortalityinmanyLMICs[4,62],and out-breakshavecontinuedtooccurinseveralhigh-incomecountries [63,64],especiallyamonggay,bisexualandothermenwhohave sexwithmenwhoareoftenco-infectedwithHIV[65].Theongoing threatposedbysyphilishighlightsthecrucialneedfor continu-ingworktodevelopaneffectivesyphilisvaccine.However,onlya limitednumberofinvestigatorsworldwideworkonsyphilis vac-cinedevelopment.Onebodyofresearchprimarilyfocusesupon decipheringthecomplexitiesassociatedwiththeprocessof anti-genicvariationwithinT.pallidumandestablishmentofpersistent andrecurrentinfection[66–69].Anotherfocusesupon trepone-mal dissemination within the host [70–73]. The goal of both areasofresearchistouseareversevaccinologyapproach, com-binedwithtargetedfunctionalstudies,tofullyunderstandcritical host–pathogeninteractionsandkeypathogenicmechanisms uti-lizedbyT.pallidum,atleastsomeofwhichappeartobenoveland exquisitelytailoredfortherequirementsofanobligatepathogen. Informationfromthesestudiesis thenusedtoidentifyoptimal syphilisvaccinetargets.
and propose a two-pronged approach topreventionof syphilis infection,wherebyavaccinecocktailofantigenscriticalfor chan-credevelopment[66–69]arecombinedwithanantigenessential fortreponemaldissemination[70–72].Suchanapproach,if suc-cessful,woulddelivera“holistic”vaccinethatstemstransmission ofsyphilis duringtheprimarystage ofinfectionviaprevention ofulcerativechancres, and simultaneouslypreventstheserious sequelae(congenitalinfection,neurosyphilis)andsecondarystage transmissionthatoccurduetotreponemaldissemination.
A path moving forward for syphilis vaccine development is vitaltoevaluatethecurrentlyavailablevaccineapproachandto attractnewinvestigatorstothefield todevelop additional vac-cinetargetsandstrategies.Advancesinsequencingofcirculating syphilisstrainscanprovideadditionalinformationonthe cross-protectivepotentialofselectedvaccinetargets[74,75].Ongoing studiesinvestigatingimmunecorrelatesassociatedwith protec-tionfromdisease,adjuvantoptimizationtoachievetheseimmune functions,andmathematicalmodelingstudiestopredicttheglobal healthimpactofasyphilisvaccinewillalsobevaluable.Widespread supportandinnovativepartnershipswillbeneededtocatalyze syphilisvaccine developmentand combata global diseasethat hasdevastatingconsequencesforreproductiveandfetal/newborn health,affectingthegeneralpopulationofmanyLMICsandkey populationsworldwide.
5. Movingforward
The STI vaccine roadmap outlines priority action steps to advance STI vaccine development. Since its publication, much progresshasbeenmadeinseveraloverarchingactivitiestoobtain betterepidemiologicdatatoestablishthepublichealthrationale and global market for these vaccines, to model thetheoretical impact of future vaccines, and to establish what is needed to definepreferredproductcharacteristicsandencourageinvestment in STI vaccine development.Severalbasic science advancesfor individualvaccineshavebenefitedfromparalleleffortsto coor-dinateandstreamlineresearchandproductdevelopmentamong investigators.ThegreatestadvanceshavebeenmadewithHSV vac-cinedevelopment,wheremultiplepromisingvaccinecandidatesin earlyclinicaltrialsprovidehopethatanHSVvaccineisonthe hori-zon.However,thefirstnewsexuallytransmittedchlamydiavaccine candidate will be entering phase I trials, and new technology advanceswillseeseveralmorevaccinecandidatesinthepipeline. Aconfluenceoffactors,suchasinternationalroll-outofHPV vaccineraisingglobalawarenessofasuccessfulSTIvaccine,the growingspecterof multidrug-resistantgonorrhea, technological advancesin antigenselection and noveladjuvants, and theSTI vaccine roadmap itself, has provided renewed enthusiasm for STI vaccine development. Interest in STI vaccine development has dovetailed with the growing movement around develop-ment of multipurposeprevention technologies, which combine various HIV, STI and pregnancy prevention features [76]. Both effortsheightenawarenessoftheimportanceofharnessingnew technologyadvancestoimprovesexualandreproductivehealth worldwide.Inordertocapitalizeonthismomentum,thegoalis toexpandonthesubstantialcollaborativeeffortsalready under-takenbytheSTIvaccinecommunitytodevelopanoverarchingSTI vaccineconsortium,withworkinggroupsforeachSTI.TheSTI vac-cineroadmapprovidesaframeworktocoordinateandstreamline activitiessothattheycontributetoalargercohesivewhole.HSV vaccinehasbeenprioritizedininitialefforts,intermsofconducting impactmodeling,generatingPPCs,anddevelopingabusinesscase, asitsresearchanddevelopmentprogramisfurthestalong.These
vaccinedevelopment.Withcontinuedsupportandcollaboration, thesemuchneededSTIvaccinescanbemadeareality.
Acknowledgments
Participants of the2013STI Vaccine Technical Consultation: PatrikBavoil(UniversityofMaryland,Baltimore,USA);GailBolan (CentersforDiseaseControlandPrevention,USA);Rebecca Brot-man(UniversityofMarylandSchoolofMedicine,USA);Nathalie Broutet(WHO,Switzerland);RobertC.Brunham(BritishColumbia CentreforDiseaseControl,Canada);CarolineE.Cameron (Univer-sityofVictoria,Canada);JaneCarlton(NewYorkUniversity,USA); Venkatraman Chandra-Mouli(WHO, Switzerland); Xiang-Sheng Chen (ChineseAcademy of Medical Sciences and Peking Union MedicalCollege,China);Zvavahera(Mike)Chirenje(Universityof Zimbabwe,Zimbabwe); CarolynDeal(NIAID, USA);BettyDodet (Dodet Biosciences, France); Peter Figueroa (University of the West Indies, Jamaica); Uli Fruth (WHO, Switzerland); Geoffrey Garnett(BillandMelindaGatesFoundation,USA);KhalilGhanem (JohnsHopkinsUniversitySchoolofMedicine,USA);SamiGottlieb (WHO, Switzerland); Patti Gravitt (Perdana University Gradu-ate School of Medicine, Malaysia); Gerardo Guillen (Center for Genetic Engineering and Biotechnology, Cuba); Sarah Hawkes (University College London, UK); Annika Hofstetter (Columbia University Medical Center, USA); Walter Jaoko (International CentreforReproductiveHealth,Kenya);AnnE.Jerse(Uniformed ServicesUniversityoftheHealthSciences,USA);Christine John-ston(UniversityofWashington,USA);NicolaLow(Universityof Bern,Switzerland);DavidMabey(LondonSchoolofHygieneand Tropical Medicine,UK); Noni MacDonald(DalhousieUniversity, Canada);FredMhalu(MuhimbiliUniversityofHealthandAllied Sciences, Tanzania); André Meheus (University of Antwerpen, Belgium);LoriNewman(WHO,Switzerland);JacquesRavel (Uni-versityofMarylandSchoolofMedicine,USA);HelenRees(Wits Reproductive Health and HIV Institute, South Africa); Anne M. Rompalo (Johns Hopkins University School of Medicine, USA); Kenneth L. Rosenthal (McMaster University, Canada); Susan L. Rosenthal (Columbia University Medical Center, USA); Michael W.Russell(UniversityofBuffalo,USA);RobinShattock(Imperial College London,UK); LawrenceStanberry (Columbia University MedicalCenter,USA);YotTeerawattananon(DepartmentofHealth Ministry of Public Health, Thailand);Peter Timms (Queensland University of Technology, Australia); Daisy Vanrompay (Ghent University,Belgium); AndreaVicari(WHO/PanAmericanHealth Organization,Costa Rica);TeodoraWi(WHO,Switzerland).The authorsalsowishtothankVittalMogasale,InternationalVaccine Institute,Korea,for hisinputontheHSVvaccinebusinesscase, andManjulaaNarasimhan,WHO,forherreviewofthemanuscript. Conflictsofintereststatement:Drs.Gottlieb,Deal,Giersing,Rees, Bolan,Timms, Gray-Owen,Jerse, Cameron,Moorthy,Kiarie, and Broutetreportnopotentialconflictsofinterest.Dr.Johnstonhas conductedresearchattheUniversityofWashingtonsponsoredby thefollowingcompaniesasaprincipalorco-investigator:Agenus, Genocea,Vical,Gilead,AiCuris,andSanofi.
Disclaimers:Drs.Gottlieb,Giersing,Moorthy,KiarieandBroutet arestaffmembersoftheWorldHealthOrganization.Theauthors aloneareresponsiblefortheviewsexpressedinthisarticleand theydonotnecessarilyrepresentthedecisionsorpoliciesofthe WorldHealthOrganization.
The findingsand conclusions of this reportare those of the authorsanddo notnecessarilyrepresenttheofficialpositionof theCentersforDiseaseControlandPrevention.
2946 S.L.Gottliebetal./Vaccine34(2016)2939–2947 References
[1]NewmanL,RowleyJ,VanderHoornS,WijesooriyaN,UnemoM,LowN,etal. Globalestimatesoftheprevalenceandincidenceoffourcurablesexually trans-mittedinfectionsin2012basedonsystematicreviewandglobalreporting. PLOSONE2015;10:e0143304.
[2]LookerKJ,MagaretAS,TurnerKM,VickermanP,GottliebSL,NewmanLM. Globalestimatesofprevalentandincidentherpessimplexvirustype2 infec-tionsin2012.PLOSONE2015;10:e114989.
[3]LookerKJ,MagaretAS,MayMT,TurnerKM,VickermanP,GottliebSL,etal. Globalandregionalestimatesofprevalentandincidentherpessimplexvirus type1infectionsin2012.PLOSONE2015;10:e0140765.
[4]NewmanL,KambM,HawkesS,GomezG,SayL,SeucA,etal.Global esti-matesofsyphilisinpregnancyandassociatedadverseoutcomes:analysisof multinationalantenatalsurveillancedata.PLOSMed2013;10:e1001396. [5]GLOBOCAN:InternationalAgencyforResearchonCancer.Cervicalcancer:
esti-matedincidence,mortalityandprevalenceworldwidein2012;2012.http:// globocan.iarc.fr/Pages/factsheetscancer.aspx[accessed10.03.16].
[6]BrunhamRC,GottliebSL,PaavonenJ.Pelvicinflammatorydisease.NEnglJMed 2015;372:2039–48.
[7]WestromL,JoesoefR,ReynoldsG,HagduA,ThompsonSE.Pelvic inflamma-torydiseaseandfertility.Acohortstudyof1,844womenwithlaparoscopically verifieddiseaseand657controlwomenwithnormallaparoscopicresults.Sex TransmDis1992;19:185–92.
[8]FreemanEE,WeissHA,GlynnJR,CrossPL,WhitworthJA,HayesRJ.Herpes sim-plexvirus2infectionincreasesHIVacquisitioninmenandwomen:systematic reviewandmeta-analysisoflongitudinalstudies.AIDS2006;20:73–83. [9]GottliebSL,LowN,NewmanLM,BolanG,KambM,BroutetN.Towardglobal
preventionofsexuallytransmittedinfections(STIs):theneedforSTIvaccines. Vaccine2014;32:1527–35.
[10]GottliebSL,XuF,BrunhamRC.ScreeningandtreatingChlamydiatrachomatis genitalinfectiontopreventpelvicinflammatorydisease:interpretationof find-ingsfromrandomizedcontrolledtrials.SexTransmDis2013;40:97–102. [11]KirkcaldyRD,BolanGA,WasserheitJN.Cephalosporin-resistantgonorrheain
NorthAmerica.JAMA2013;309:185–7.
[12]LowN,BroutetN,Adu-SarkodieY,BartonP,HossainM,HawkesS.Global controlofsexuallytransmittedinfections.Lancet2006;368:2001–16. [13]Sexuallytransmittedinfections:vaccinedevelopmentforglobalhealth.
Vac-cine2014;32:1523–640.
[14]BroutetN,FruthU,DealC,GottliebSL,ReesH,ParticipantsoftheSTIVaccine TechnicalConsultation.Vaccinesagainstsexuallytransmittedinfections:the wayforward.Vaccine2014;32:1630–7.
[15]DodetB.Currentbarriers,challengesandopportunitiesforthedevelopmentof effectiveSTIvaccines:pointofviewofvaccineproducers,biotechcompanies andfundingagencies.Vaccine2014;32:1624–9.
[16]GlobalBurdenof DiseaseStudy 2013Collaborators.Global,regional,and nationalincidence,prevalence,andyearslivedwithdisabilityfor301acute andchronicdiseasesandinjuriesin188countries,1990–2013:a system-aticanalysisfortheGlobalBurdenofDiseaseStudy2013.Lancet2015;386: 743–800.
[17]GBD2013MortalityandCausesofDeathCollaborators.Global,regional,and nationalage-sexspecificall-causeandcause-specificmortalityfor240causes ofdeath,1990–2013:asystematicanalysisfortheGlobalBurdenofDisease Study2013.Lancet2015;385:117–71.
[18]MorrisonCS,ChenPL,KwokC,BaetenJM,BrownJ,CrookAM,etal.Hormonal contraceptionandtheriskofHIVacquisition:anindividualparticipantdata meta-analysis.PLOSMed2015;12:e1001778.
[19]AlsallaqRA,SchifferJT,LonginiJrIM,WaldA,CoreyL,Abu-RaddadLJ. Pop-ulationlevelimpactofanimperfectprophylacticvaccineforherpessimplex virus-2.SexTransmDis2010;37:290–7.
[20]FreemanEE,WhiteRG,BakkerR,OrrothKK,WeissHA,BuveA,etal. Population-leveleffectofpotentialHSV2prophylacticvaccinesonHIVincidencein sub-SaharanAfrica.Vaccine2009;27:940–6.
[21]GarnettGP.Thetheoreticalimpactofvaccinesthatprotectagainstsexually transmittedinfectionsanddisease.Vaccine2014;32(14):1536–42.
[22]Pressrelease:TheBill&MelindaGatesFoundationtofunddisease surveil-lancenetworkinAfricaandAsiatopreventchildhoodmortalityandhelp prepareforthenextepidemic;2015. http://www.gatesfoundation.org/Media- Center/Press-Releases/2015/05/Child-Health-and-Mortality-Prevention-Surveillance-Network[accessed10.03.16].
[23]Owusu-Edusei Jr K, Chesson HW, Gift TL, Brunham RC, Bolan G. Cost-effectivenessofChlamydiavaccinationprogramsforyoungwomen.Emerg InfectDis2015;21:960–8.
[24]Knipe DM,Corey L, Cohen JI,Deal CD. Summary and recommendations fromaNationalInstituteofAllergyandInfectiousDiseases(NIAID) work-shopon“NextGenerationHerpesSimplexVirusVaccines”.Vaccine2014;32: 1561–2.
[25]WorldHealthOrganization.WHOpreferredproductcharacteristics;2014. http://www.who.int/immunization/research/vaccinepreferredproduct characteristics/en/[accessed10.03.16].
[26]WorldHealthOrganization.WHOpreferredproductcharacteristics(PPC)for malariavaccines.Geneva,Switzerland:WHO;2014.http://apps.who.int/iris/ bitstream/10665/149822/1/WHOIVB14.09eng.pdf[accessed10.03.16]. [27]JohnstonC,GottliebSL,WaldA.Statusofvaccineresearchanddevelopmentof
vaccinesforherpessimplexvirus.Vaccine2016[inthisissue].
[28]MaseseL,BaetenJM,RichardsonBA,BukusiE,John-StewartG,GrahamSM, etal.ChangesinthecontributionofgenitaltractinfectionstoHIVacquisition amongKenyanhigh-riskwomenfrom1993to2012.AIDS2015;29:1077–85. [29]BelsheRB,LeonePA,BernsteinDI,WaldA,LevinMJ,StapletonJT,etal.Efficacy
resultsofatrialofaherpessimplexvaccine.NEnglJMed2012;366:34–43. [30]BernsteinDI,BellamyAR,Hook3rdEW,LevinMJ,WaldA,EwellMG,etal.
Epi-demiology,clinicalpresentation,andantibodyresponsetoprimaryinfection withherpessimplexvirustype1andtype2inyoungwomen.ClinInfectDis 2013;56:344–51.
[31]BelsheRB,HeinemanTC,BernsteinDI,BellamyAR,EwellM,vanderMostR, etal.CorrelateofimmuneprotectionagainstHSV-1genitaldiseasein vacci-natedwomen.JInfectDis2014;209:828–36.
[32]Bernard M-C,Barban V,PradezynskiF, deMontfort A,RyallR, CailletC, et al. Immunogenicity, protectiveefficacy, and non-replicative status of theHSV-2vaccinecandidateHSV529inmiceandguineapigs.PLOSONE 2015;10:e0121518.
[33]deBruynG,Vargas-CortezM,WarrenT,TyringSK,FifeKH,LalezariJ,etal. Arandomizedcontrolledtrialofareplicationdefective(gHdeletion)herpes simplexvirusvaccineforthetreatmentofrecurrentgenitalherpesamong immunocompetentsubjects.Vaccine2006;24:914–20.
[34]AgyemangAE,MagaretAS,SelkeS,JohnstonC,CoreyL,WaldA.HSVshedding: biomarkerfordiseaseseverityandresponsetoantivirals.SanDiego,CA:ID Week2015;2015.
[35]WaldA,BernsteinD,FifeK,LeeP,TyringS,VanWagonerN,etal.Novel ther-apeuticvaccineforgenitalherpesreducesgenitalHSV-2shedding.In:53rd Interscienceconferenceonantimicrobialagentsandchemotherapy.2013. [36]DuttonJL,LiB,WooW-P,MarshakJO,XuY,HuangM.-L.,etal.AnovelDNA
vaccinetechnologyconveyingprotectionagainstalethalherpessimplexviral challengeinmice.PLOSONE2013;8:e76407.
[37]VeselenakRL,ShlapoberskyM,PylesRB,WeiQ,SullivanSM,BourneN.A Vaxfectin®-adjuvantedHSV-2plasmidDNAvaccineiseffectivefor
prophy-lacticandtherapeuticuseintheguineapigmodelofgenitalherpes.Vaccine 2012;30:7046–51.
[38]Kolb AW, Larsen IV, Cuellar JA, Brandt CR. Genomic, phylogenetic, and recombinationalcharacterizationofherpessimplexvirus2strains.JVirol 2015;89:6427–34.
[39]NewmanRM,LamersSL,WeinerB,RaySC,ColgroveRC,DiazF,etal.Genome sequencingandanalysisofgeographicallydiverseclinicalisolatesofherpes simplexvirus2.JVirol2015;89:8219–32.
[40]SzparaML,GathererD,OchoaA,GreenbaumB,DolanA,BowdenRJ,etal. Evolution anddiversity inhuman herpessimplex virusgenomes.JVirol 2014;88:1209–27.
[41]LamersSL,NewmanRM,LaeyendeckerO,TobianAA,ColgroveRC,RaySC,etal. Globaldiversitywithinandbetweenhumanherpesvirus1and2glycoproteins. JVirol2015;89:8206–18.
[42]CairnsTM,HuangZ-Y,GallagherJR,LinY,LouH,WhitbeckJC,etal. Patient-specificneutralizingantibodyresponsestoherpessimplexvirusareattributed toepitopesongD,gB,orbothandcanbetypespecific.JVirol2015;89:9213–31. [43]ZhuJ,PengT,JohnstonC,PhasoukK,KaskAS,KlockA,etal.Immune surveil-lancebyCD8␣␣+skin-residentTcellsinhumanherpesvirusinfection.Nature 2013;497:494–7.
[44]WangY,KahaneS,CutcliffeLT,SkiltonRJ,LambdenPR,ClarkeIN. Develop-mentofatransformationsystemforChlamydiatrachomatis:restorationof glycogenbiosynthesisbyacquisitionofaplasmidshuttlevector.PLoSPathog 2011;7:e1002258.
[45]HuangY,ZhangQ,YangZ,ConradT,LiuY,ZhongG.Plasmid-encodedPgp5is asignificantcontributortoChlamydiamuridaruminductionofhydrosalpinx. PLOSONE2015;10:e0124840.
[46]KokesM,DunnJD,GranekJA,NguyenBD,BarkerJR,ValdiviaRH,etal. Inte-gratingchemicalmutagenesisandwhole-genomesequencingasaplatform for forwardandreversegeneticanalysisofChlamydia.CellHostMicrobe 2015;17:716–25.
[47]NguyenB,ValdiviaR.Achemicalmutagenesisapproachtoidentifyvirulence determinantsintheobligateintracellularpathogenChlamydiatrachomatis. MethodsMolBiol2014;1197:347–58.
[48]NguyenBD,ValdiviaRH.ForwardgeneticapproachesinChlamydiatrachomatis. JVisExp2013:e50636.
[49]ChenJ,YangZ,SunX,TangL,DingY,XueM,etal.Intrauterineinfectionwith plasmid-freeChlamydiamuridarumrevealsacriticalroleoftheplasmidin chla-mydialascensionandestablishesamodelforevaluatingplasmid-independent pathogenicity.InfectImmun2015;83:2583–92.
[50]KariL,WhitmireWM,Olivares-ZavaletaN,GoheenMM,TaylorLD,Carlson JH,etal.Alive-attenuatedchlamydialvaccineprotectsagainsttrachomain nonhumanprimates.JExpMed2011;208:2217–23.
[51]QuY,FrazerLC,O’ConnellCM,TarantalAF,AndrewsJrCW,O’ConnorSL, etal.Comparablegenitaltractinfection,pathology,andimmunityinrhesus macaquesinoculatedwithwild-typeorplasmid-deficientChlamydia tracho-matisserovarD.InfectImmun2015;83:4056–67.
[52]BojeS,OlsenAW,ErneholmK,AgerholmJS,JungersenG,AndersenP,etal.A multi-subunitChlamydiavaccineinducingneutralizingantibodiesandstrong IFN-gammaCMIresponsesprotectsagainstagenitalinfectioninminipigs. ImmunolCellBiol2015;94:185–95.
[53]StatensSerumInstitut.Chlamydiavaccineresearch;2016.http://www.ssi.dk/ English/RandD/Research%20areas/Vaccines/Chlamydia%20Vaccine% 20Research.aspx[accessed10.03.16].
[55]JerseAE.Experimentalgonococcalgenitaltractinfectionandopacityprotein expressioninestradiol-treatedmice.InfectImmun1999;67:5699–708. [56]Liu Y, IslamEA, JarvisGA, Gray-OwenSD,Russell MW. Neisseria
gonor-rhoeaeselectively suppressesthedevelopmentofTh1 andTh2cells,and enhances Th17 cellresponses,through TGF-beta-dependentmechanisms. MucosalImmunol2012;5:320–31.
[57]LiuY,EgilmezNK,RussellMW.EnhancementofadaptiveimmunitytoNeisseria gonorrhoeaebylocalintravaginaladministrationofmicroencapsulatedIL-12.J InfectDis2013;208:1821–9.
[58]StupianskyNW,VanDerPolB,WilliamsJA,WeaverB,TaylorSE,Fortenberry JD.Thenaturalhistoryofincidentgonococcalinfectioninadolescentwomen. SexTransmDis2011;38:750–4.
[59]EzewudoMN,JosephSJ,Castillo-RamirezS,DeanD,DelRioC,DidelotX,etal. PopulationstructureofNeisseriagonorrhoeaebasedonwholegenomedataand itsrelationshipwithantibioticresistance.PeerJ2015;3:e806.
[60]McClureR,NudelK,MassariP,TjadenB,SuX,RicePA,etal.Thegonococcal transcriptomeduringinfectionofthelowergenitaltractinwomen.PLOSONE 2015;10:e0133982.
[61]HobbsMM,AndersonJE,BalthazarJT,KandlerJL,CarlsonRW,GangulyJ,etal. LipidA’sstructuremediatesNeisseriagonorrhoeaefitnessduringexperimental infectionofmiceandmen.MBio2013;4:e00892–913.
[62]LawnJE,BlencoweH,WaiswaP,AmouzouA,MathersC,HoganD,etal. Still-births:rates,riskfactors,andaccelerationtowards2030.Lancet387,2016, 587-603.
[63]D’Angelo-ScottH,CutlerJ,FriedmanD,HendriksA,JollyAM.Socialnetwork investigationofasyphilisoutbreakinOttawa,Ontario.CanJInfectDisMed Microbiol2015;26:268–72.
[64]Mayor S. Syphilis and gonorrhoea increase sharply in England. BMJ 2015;350:h3457.
[65]ReadP,FairleyCK,ChowEP.Increasingtrendsofsyphilisamongmenwhohave sexwithmeninhighincomecountries.SexHealth2015;12:155–63. [66]Centurion-LaraA,CastroC,BarrettL,CameronC,MostowfiM,VanVoorhis
WC,etal.TreponemapallidummajorsheathproteinhomologueTprKisa
Fineanalysisofgeneticdiversityofthetprgenefamilyamongtreponemal species,subspeciesandstrains.PLoSNeglTropDis2013;7:e2222.
[68]Centurion-LaraA,GodornesC,CastroC,VanVoorhisWC,LukehartSA.ThetprK geneisheterogeneousamongTreponemapallidumstrainsandhasmultiple alleles.InfectImmun2000;68:824–31.
[69]GiacaniL,MoliniBJ,KimEY,GodornesBC,LeaderBT,TantaloLC,etal. Anti-genicvariationinTreponemapallidum:TprKsequencediversityaccumulates inresponsetoimmunepressureduringexperimentalsyphilis.JImmunol 2010;184:3822–9.
[70]CameronCE,BrouwerNL,TischLM,KuroiwaJM.Definingtheinteraction of the Treponema pallidum adhesinTp0751 with laminin. Infect Immun 2005;73:7485–94.
[71]HoustonS,HofR, FrancescuttiT,Hawkes A,Boulanger MJ,CameronCE. Bifunctionalrole ofthe Treponema pallidumextracellular matrixbinding adhesinTp0751.InfectImmun2011;79:1386–98.
[72]HoustonS,HofR,HoneymanL,HasslerJ,CameronCE.Activationand pro-teolyticactivityoftheTreponemapallidummetalloprotease,pallilysin.PLoS Pathog2012;8:e1002822.
[73]HoustonS,TaylorJS,DenchevY,HofR,ZuernerRL,CameronCE. Conserva-tionofthehost-interactingproteinsTp0750andpallilysinamongtreponemes andrestrictionofproteolyticcapacitytoTreponemapallidum.InfectImmun 2015;83:4204–16.
[74]CejkovaD,StrouhalM,NorrisSJ,WeinstockGM,SmajsD.Aretrospective studyongeneticheterogeneitywithinTreponemastrains:subpopulationsare geneticallydistinctinalimited numberofpositions.PLoS NeglTropDis 2015;9:e0004110.
[75]NechvatalL,PetrosovaH,GrillovaL,PospisilovaP,MikalovaL,StrnadelR,etal. Syphilis-causingstrainsbelongtoseparateSS14-likeorNichols-likegroups asdefinedbymultilocusanalysisof19Treponemapallidumstrains.IntJMed Microbiol2014;304:645–53.
[76]Fernandez-RomeroJA,DealC,HeroldBC,SchillerJ,PattonD,ZydowskyT,etal. Multipurposepreventiontechnologies:thefutureofHIVandSTIprotection. TrendsMicrobiol2015;23:429–36.