ImpactImpact ofof ConjugateConjugate PneumococcalPneumococcal VaccineVaccine onon PneumococcalPneumococcal Pneumonia:Pneumonia: ImplicationsImplications forfor PandemicPandemic InfluenzaInfluenza PreparednessPreparedness KeithKeith P.P. KlugmanKlugman

DepartmentDepartment ofof GlobalGlobal Health,Health, RollinsRollins SchoolSchool ofof PublicPublic HealthHealth andand DivisionDivision ofof InfectiousInfectious Diseases,Diseases, SchoolSchool ofof MedicineMedicine EmoryEmory University,University, Atlanta,Atlanta, USAUSA AcuteAcute respiratoryrespiratory infectionsinfections –– thethe leadingleading infectiousinfectious causecause ofof deathdeath 4.0 3.5

3.0 Over age five Under age five 2.5 * HIV-positive people 2.0 who have died with TB have been 1.5 included among AIDS deaths Millions of deaths 1.0

0.5

0 Acute AIDS* Diarrhoeal TB Malaria Measles respiratory diseases infections Estimates for adults 2002; under 5’s 2000-2003; World Health Report 2004/52 CommunityCommunity AcquiredAcquired PneumoniaPneumonia frequencyfrequency byby ageage // 10001000 40

35

30

25

20

15

10

5

0 << 55 55 -- 14 14 1515 -- 29 29 3030 -- 44 44 4545 -- 59 59 6060 -- 74 74 >> 7474 AgeAge (years)(years)

Jokinen et al. Am J Epidemiol 1993;137:977-988 Jokinen et al. Am J Epidemiol 1993;137:977-988 3 BacterialBacterial EtiologyEtiology ofof CommunityCommunity-- AcquiredAcquired PneumoniaPneumonia Atypical pathogens: Legionella spp S. pneumoniae Chlamydia spp Mycoplasma spp 22% 34%

6% S. aureus

15% 15% Other 8% H. influenzae and M. catarrhalis Aerobic gram-negative rods

Cunha BA. Chest. 2004;125:1913-1919; American Thoracic Society. Am J Respir Crit Care Med. 2001;163:1730-1754. 4 EtiologicalEtiological RoleRole ofof BacteriaBacteria inin PneumoniaPneumonia „ OurOur toolstools toto definedefine aa bacterialbacterial etiologyetiology inin pneumoniapneumonia areare insensitiveinsensitive „ BloodBlood cultureculture identifiesidentifies lessless thanthan 10%10% ofof presumedpresumed bacterialbacterial pneumonia.pneumonia. „ LungLung puncture,puncture, BALBAL andand protectedprotected specimenspecimen brushbrush techniquestechniques areare rarelyrarely donedone andand areare overlyoverly invasive.invasive. „ SerologicalSerological teststests havehave beenbeen confoundedconfounded byby lacklack ofof specificityspecificity „ UrineUrine antigenantigen isis promisingpromising inin adultsadults butbut isis confoundedconfounded byby NPNP carriagecarriage inin childrenchildren „ PCRPCR hashas notnot toto datedate realizedrealized aa sensitivitysensitivity greatergreater thanthan thatthat ofof cultureculture 5 VaccineVaccine asas aa ProbeProbe toto DefineDefine thethe AetiologyAetiology ofof PneumoniaPneumonia

„ WhileWhile thethe adultadult 2323 valentvalent vaccinevaccine hashas notnot beenbeen shownshown inin randomizedrandomized trialstrials ofof thethe elderlyelderly toto preventprevent clinicalclinical oror XX--rayray confirmedconfirmed pneumonia,pneumonia, recentrecent datadata suggestsuggest thatthat conjugateconjugate vaccinesvaccines maymay dodo soso inin children.children. „ HaemophilusHaemophilus typetype BB conjugateconjugate vaccinevaccine hashas beenbeen shownshown toto impactimpact onon pneumoniapneumonia „ TheseThese vaccinesvaccines maymay thusthus toto usedused asas probesprobes toto definedefine thethe rolerole ofof bacteriabacteria inin thethe etiologyetiology ofof pneumonia.pneumonia.

6 ALVEOLARALVEOLAR CONSOLIDATIONCONSOLIDATION

7 EfficacyEfficacy ofof HaemophilusHaemophilus influenzaeinfluenzae PRPPRP –– TT ConjugateConjugate VaccineVaccine inin thethe PreventionPrevention ofof PneumoniaPneumonia

„ 100%100% efficacyefficacy againstagainst bacteremicbacteremic pneumoniapneumonia (95%(95% CICI 5555 –– 100)100) „ 25.2%25.2% reductionreduction inin lobarlobar consolidationconsolidation withwith effusioneffusion (95%(95% CICI 0.20.2 –– 44.1)44.1) „ 21.1%21.1% reductionreduction inin allall radiologicallyradiologically provenproven pneumoniapneumonia (95%(95% CICI 4.64.6 –– 34.9)34.9)

Mulholland et al, Lancet 1997; 349: 1191 – 97.

8 Prevention of Pneumonia in Children 4-23 months by PRP-T, Chile

C,E C,E,ESR C,E,BB C,E,ESR,BB

C, consolidation or E, effusion, or ESR>40mm, or BB, bronchial breathing

Levine et al, PIDJ, 1999;18:1060-1064 9 EffectivenessEffectiveness ofof HibHib AgainstAgainst PneumoniaPneumonia –– otherother studiesstudies „ BrazilBrazil –– CaseCase controlcontrol -- radiographicallyradiographically confirmedconfirmed pneumoniapneumonia byby WHOWHO criteriacriteria „ ConfoundersConfounders thatthat increasedincreased riskrisk inin casescases werewere fluflu –– likelike illnessillness inin pastpast 22 weeks,weeks, dayday –– carecare attendance,attendance, smokerssmokers atat home,home, andand lowerlower SESSES „ ControllingControlling forfor thethe aboveabove inin multivariatemultivariate analysisanalysis VEVE waswas 31%31% ((--9%9% -- 57%)57%) „ Lombok,Lombok, IndonesiaIndonesia –– nono efficacyefficacy againstagainst radiologicallyradiologically confirmed,confirmed, oror severe,severe, hospitalizedhospitalized pneumoniapneumonia –– 4%4% protectionprotection againstagainst highhigh burdenburden ofof clinicalclinical pneumoniapneumonia De Andrade et al, Int J Epidemiol, 2004, 33, 173 -81 Gessner et al, Lancet, 2005, 365, 43 - 52 10 PerPer ProtocolProtocol VaccineVaccine EfficacyEfficacy –– PneumoniaPneumonia –– CaliforniaCalifornia –– KidsKids << 55 YearsYears ofof AgeAge Cases / 1000 Cases / 1000 Vaccine 95% confidence person years person years efficacy interval in control in vaccine group group All clinical pneumonia 55.9 53.4 4.3 -3.5 – 11.5 Radiograph obtained 34.2 30.9 9.8 0.1 – 18.5 Point of Care Reading of 11.0 8.7 20.5 4.4 – 34.0 Consolidation WHO - - 30.3 10.7 – 45.7 Consolidation

Black et al, PIDJ, 2002, 21, 810 – 15; Hansen et al, PIDJ, 2006, 25, 779-81. 11 VaccineVaccine EfficacyEfficacy AgainstAgainst VaccineVaccine--SerotypeSerotype SpecificSpecific IPDIPD InIn HIVHIV InfectedInfected (No(No ARV)ARV) andand HIVHIV UninfectedUninfected ChildrenChildren

Incidence* Incidence* Efficacy VAR* Vaccinees Controls (95%CI) HIV Neg 7 39 83 (39, 97) 32

HIV Pos 300 870 65 (24, 86) 570

•Per 100 000 child years * VAR=Number of cases prevented per 100 000 child years Klugman KP et al NEJM 2003 12 VaccineVaccine EfficacyEfficacy –– FirstFirst EpisodeEpisode Pneumonia*Pneumonia* –– HIVHIV--veve CasesCases inin CasesCases inin VaccineVaccine 95%95% controlcontrol vaccinevaccine efficacyefficacy confidenceconfidence groupgroup groupgroup intervalinterval

ITTITT 212212 169169 2020 22 -- 3535

PPPP 158158 119119 2525 44 –– 4141

* Pneumonia is defined by CXR findings of consolidation based on the WHO consensus document Klugman et al, NEJM, 2003, 349, 1341-8 13 VaccineVaccine EfficacyEfficacy AgainstAgainst RadiologicallyRadiologically ConfirmedConfirmed PneumoniaPneumonia

Incidence* Incidence Efficacy VAR* Vaccinees Controls* (95%CI) SA: HIV Neg 390 490 20 (3, 35) 100 SA: HIV Pos 7 910 7 000 13 (-7, 28) 910

* Per 100 000 child years VAR= Number of cases prevented per 100 000 child years

Klugman KP et al. NEJM 2003 14 VaccineVaccine EfficacyEfficacy AgainstAgainst AllAll LowerLower RespiratoryRespiratory TractTract InfectionInfection

Incidence* Incidence Efficacy VAR* Vaccinees Controls (95%CI) SA: HIV Neg 2 400 2 570 7 (-1; 14) 170 SA: HIV Pos 14 150 16 720 15 (6, 24) 2 570

* Per 100 000 child years VAR= Number of cases prevented per 100 000 child years

Madhi SA et al. Clin Infect Dis 2005 15 CRPCRP isis UsefulUseful toto DefineDefine PneumococcalPneumococcal PneumoniaPneumonia inin ChildrenChildren withwith LRTILRTI andand NONO ConsolidationConsolidation oror EffusionEffusion onon CXRCXR „ InIn HIVHIV uninfecteduninfected childrenchildren efficacyefficacy inin thisthis groupgroup withwith LRTILRTI waswas 2%(NS),2%(NS), butbut 32%32% (P(P == 0.007)0.007) inin thosethose withwith CRPCRP >> 4040 „ InIn HIVHIV infectedinfected childrenchildren efficacyefficacy inin thisthis groupgroup withwith LRTILRTI waswas 13%(NS)13%(NS) butbut 31%31% (P(P == 0.03)0.03) inin thosethose withwith CRPCRP >> 4040

Madhi, Kohler, Kuwanda, Cutland, Klugman, PIDJ, 2006, 25, 30 - 36 16 TheThe MostMost SensitiveSensitive DetectionDetection ofof PneumococcalPneumococcal DiseaseDisease inin InfantsInfants isis AnyAny InfiltrateInfiltrate onon CXRCXR PlusPlus CRPCRP >40>40 mg/Lmg/L CXRCXR -- ACAC VARVAR 100100

CXRCXR NoNo ACAC VARVAR 205205 CRPCRP >> 4040 CXRCXR ––ACAC ++ VARVAR 350350 AnyAny infiltrateinfiltrate CRPCRP >> 4040 Madhi & Klugman, Vaccine, 2007, in press 17 EfficacyEfficacy ofof 99--valentvalent ConjugateConjugate -- GambiaGambia (Per(Per Protocol)Protocol) Endpoint Vaccine Placebo Vaccine Efficacy n=8189 n=8151 (95% CI) Radiological pneumonia 207 323 37 (25 to 48) Clinical pneumonia 2172 2284 7 (1 to 12) Severe clinical pneumonia 172 192 12 (-9 to 29) VT invasive disease 9 38 77 (51 to 90) VT lung aspirate 3 11 73 (-2 to 95) Hospital admission 1065 1216 15 (7 to 21) All cause mortality 330 389 16 (3 to 28)

Cutts et al, Lancet, 2005, 365, 1139 - 46 18 Differences in rates of pneumococcal and nonspecific pneumonia, otitis media, and other ARI visits in children <2 years old after the introduction of PCV7: US ambulatory settings

Grijalva, C. G. et al. Pediatrics 2006;118:865-873

Copyright ©2006 American Academy of Pediatrics 19 Case Control Study of Risk Factors for Pneumococcal Bacteremia

Nuorti et al, N Engl J Med, 2000, 342, 681-9.

20 Contact with a Child as a Risk for Pneumococcal Bacteremia in HIV Infected Patients

Cases were HIV infected patients with pneumococcal bacteremia and controls were also HIV infected admitted to the same hospital and matched by CD4 count or AIDS clinical stage.

Breiman et al, Arch Int Med, 2000, 160, 2633-8 21 Increasing Pediatric Serotypes with Age > 65 in Adults

Feikin, Klugman et al, CID, 2005, 41,481-7 22 FamilyFamily TransmissionTransmission ofof ResistantResistant PneumococciPneumococci

„ ““TransmissionTransmission ofof StreptococcusStreptococcus pneumoniaepneumoniae betweenbetween childrenchildren andand theirtheir parentsparents waswas evaluatedevaluated inin 2929 pairspairs fromfrom 2525 families,families, inin whomwhom thethe indexindex casecase waswas anan adultadult withwith invasiveinvasive pneumococcalpneumococcal infectioninfection.. „ TheThe serotypesserotypes ofof 3535 pneumococcalpneumococcal isolatesisolates fromfrom 1818 (62.1%)(62.1%) ofof 2929 childchild--parentparent pairspairs werewere identical.identical. „ MolecularMolecular typingtyping byby pulsedpulsed--fieldfield gelgel electrophoresiselectrophoresis showedshowed thatthat 1212 pairspairs werewere indistinguishable,indistinguishable, 33 pairspairs werewere closelyclosely related,related, 22 pairspairs werewere possiblypossibly related,related, andand onlyonly oneone pairpair waswas different.different. „ DataData indicateindicate thethe presencepresence ofof aa highhigh raterate ofof transmissiontransmission ofof penicillinpenicillin--resistantresistant S.S. pneumoniaepneumoniae betweenbetween childrenchildren andand theirtheir parentsparents””

Hoshino K, et al. J Clin Microbiol 2002; 40: 4357 – 4359. 23 MMWR, Sep 16, 2005, 893 - 897 24 MMWR, Sep 16, 2005, 893 - 897 25 Grijalva et al, Lancet, 2007, 369,1179-86 US Hospital Admissions

26 PCV7 Impact on Pneumonia in the USA

Grijalva et al, Lancet, 2007, 369,1179-86

27 SerologicSerologic andand PCRPCR AssaysAssays DocumentDocument aa MixedMixed Viral/BacterialViral/Bacterial EtiologyEtiology inin HospitalizedHospitalized ChildrenChildren withwith PneumoniaPneumonia

„ 30%30% ofof 254254 childrenchildren hadhad evidenceevidence ofof mixedmixed bacterialbacterial // viralviral infectioninfection Juven et al, PIDJ, 2000, 19, 293-8 „ SerologicalSerological evidenceevidence ofof bacterialbacterial infectioninfection waswas foundfound inin 00 ofof 2424 childrenchildren withwith PIVPIV andand croupcroup butbut inin 44 // 1313 (31%)(31%) withwith PIVPIV andand LRTLRT Korppi et al, Scand J Infect Dis, 1990, 22, 307 - 12 „ BacterialBacterial serologyserology waswas positivepositive inin 39%39% ofof hospitalizedhospitalized childrenchildren withwith RSVRSV infectioninfection andand pneumoniapneumonia oror otitisotitis Korppi et al, PIDJ, 1989, 10, 687 – 92 „ 31%31% ofof episodesepisodes ofof pneumococcalpneumococcal communitycommunity acquiredacquired pneumoniapneumonia diagnoseddiagnosed byby cultureculture andand PCRPCR werewere coco –– infectedinfected withwith aa virusvirus Michelow et al, Pediatrics, 2004, 113, 701-7 28 Fatalities

Probablility (%) Smil V, Pop Dev Rev, 2005, 31, 201-36 29 Synergistic Lethality of Influenza plus Pneumococci Given 7 Days Later in Mice

Peltola and McCullers, PIDJ, 2004,23,S87-97 0.05 MLD flu and 0.002 MLD pneumo

McCullers and Rehg, JID, 2002, 186, 341-350 0.3 MLD flu and 0.2 MLD pneumo Pneumococcus followed by influenza virus PBS followed by pneumococcus PBS followed by influenza virus

PBS followed by pneumococcus and influenza virus together

Influenza virus followed by pneumococcus.

30 PnCV Efficacy Against Viral Pneumonia – All Children Fully Immunized

Virus Cases Controls Vaccine efficacy P (95% CI) Influenza 31 56 45 (14 - 64) 0.01

RSV 90 115 22 (-3 - 41) 0.08

Parainfluenza 24 43 44 (8 - 66) 0.02

Adenovirus 14 15 7 (-94 - 55) 0.9

Any of the 160 231 31 (15 – 43) 0.0004 above No virus 419 486 14 (2 – 24) 0.03 isolated Madhi, Klugman et al, Nature Medicine, 2004, 10, 811 -13 31 ImpactImpact ofof ConjugateConjugate VaccineVaccine onon HumanHuman MetapneumovirusMetapneumovirus AssociatedAssociated PneumoniaPneumonia

Madhi et al, JID, May 2006, 193, 1236 -1243 32 Black October: The Impact of the Spanish Influenza Epidemic of 1918 on South Africa (Archives year book for South African history) by H Phillips

33 DidDid BacterialBacterial InfectionInfection (esp.(esp. thethe Pneumococcus)Pneumococcus) PlayPlay aa MajorMajor RoleRole inin MortalityMortality DuringDuring thethe 19181918 InfluenzaInfluenza Epidemic?Epidemic?

34 ILI Followed by Pneumonia and/or Death

Opie et al, JAMA, 1919, 72 , 556–565; Synnott and Clark, JAMA, 1918, 71, 1816–1821; in Brundage, Lancet ID, 2006, 6, 303-12 35 Timeline Post Infection of Influenza Deaths – 1918 Epidemic

Mills et al, Nature, 2004, 432, 904 – 6, Supplementary fig 2 36 19181918 InfluenzaInfluenza Epidemic.Epidemic. HeartHeart BloodBlood CulturesCultures PostPost MortemMortem „ InIn ninenine postpost--mortemmortem examinationsexaminations atat CampCamp Logan,Logan, TxTx,, pneumococcipneumococci werewere thethe mostmost frequentlyfrequently recoveredrecovered organismsorganisms fromfrom lungslungs (44%),(44%), pleuralpleural cavitiescavities (67%),(67%), andand heartheart bloodblood (33%)(33%) Hall et al, 1918, JAMA, 71,1986–1987 „ PneumococciPneumococci werewere isolatedisolated fromfrom 65%65% ofof 8080 postpost--mortemmortem culturescultures ofof heartheart bloodblood atat CampCamp DevensDevens,, MAMA Spooner et al, JAMA, 1919, 72, 155–159 „ PostPost--mortemmortem culturescultures ofof lunglung andand heartheart bloodblood specimensspecimens fromfrom 280280 fatalfatal pneumoniapneumonia casescases atat CampCamp Custer,Custer, MI,MI, revealedrevealed thatthat 28%28% ofof eacheach werewere positivepositive forfor pneumococcuspneumococcus Blanton and Irons, 1918, JAMA, 71, 1988–1991 37 19181918 InfluenzaInfluenza Epidemic.Epidemic. BloodBlood CulturesCultures fromfrom LivingLiving PatientsPatients

„ BloodBlood culturescultures werewere mademade fromfrom 1515 severesevere presumedpresumed influenzainfluenza casescases inin BritishBritish andand AmericanAmerican troopstroops –– 55 (33%)(33%) grewgrew pneumococcipneumococci Muir and Wilson, BMJ, 1919, 1, 3-5 „ 4545 ofof 9090 bloodblood culturescultures ofof livingliving patientspatients atat CampCamp Grant,Grant, IL,IL, revealedrevealed ““aa GramGram--positivepositive diplococcusdiplococcus inin purepure strainstrain withoutwithout exceptionexception …… allall thethe morphologicmorphologic andand culturalcultural characteristicscharacteristics ofof aa pneumococcuspneumococcus”” Hirsch and McKinney, 1918, JAMA, 71, 1735–1736

38 DidDid BacteriaBacteria PlayPlay aa RoleRole inin thethe 19181918 InfluenzaInfluenza Epidemic?Epidemic?

„ ““NoNo oneone doubtsdoubts thatthat epidemicepidemic influenzainfluenza isis duedue toto aa specificspecific organism,organism, yetyet inin hardlyhardly anyany otherother diseasedisease dodo wewe meetmeet withwith suchsuch aa varietyvariety ofof lesionslesions andand complications,complications, producedproduced byby variousvarious organismsorganisms ofof commoncommon occurrenceoccurrence apartapart fromfrom influenza.influenza. ApparentlyApparently thethe explanationexplanation isis thatthat thethe specificspecific organismorganism leadsleads toto aa diminisheddiminished resistanceresistance ofof thethe bronchialbronchial mucosa,mucosa, andand thusthus bacterialbacterial growthgrowth extendsextends toto thethe finestfinest tubules,tubules, andand bronchopneumoniabronchopneumonia frequentlyfrequently followsfollows”” Muir and Wilson, BMJ, 1919, 1, 3-5

39 Klugman and Madhi, Science, 2007, 316, 49 – 50. 40 Advanced Market Commitment

41 ConclusionsConclusions

„ PCVPCV hashas demonstrateddemonstrated thatthat itit cancan bebe usedused asas aa probeprobe toto definedefine thethe burdenburden ofof pneumococcalpneumococcal pneumoniapneumonia „ PCVPCV vaccinevaccine hashas reducedreduced thethe morbiditymorbidity andand mortalitymortality ofof pneumoniapneumonia inin childrenchildren andand maymay reducereduce pneumoniapneumonia amongamong adultsadults byby herdherd immunityimmunity „ PCVPCV maymay reducereduce thethe mortalitymortality andand morbiditymorbidity associatedassociated withwith viralviral respiratoryrespiratory infectionsinfections includingincluding pandemicpandemic influenzainfluenza andand shouldshould bebe consideredconsidered togethertogether withwith PPVPPV asas anan essentialessential partpart ofof pandemicpandemic fluflu planningplanning 42