Efficacy and Effectiveness of the PCV-10 and PCV-13 ...

Efficacy and Effectiveness of thePCV-10 and PCV-13 Vaccines AgainstInvasive Pneumococcal DiseaseMelissa Berman-Rosa, MScPH,a,b Shauna O’Donnell, MSc,a,b,c Mackenzie Barker, BSc,d Caroline Quach, MD, MSca,b,c,e

abstractCONTEXT: Pneumococcal conjugate vaccines (PCVs) (pneumococcal 13-valent conjugate vaccine [PCV-13] andpneumococcal 10-valent conjugate vaccine [PCV-10]) are available for prevention of pneumococcalinfections in children.

OBJECTIVE: To determine the vaccine effectiveness (VE) of PCV-13 and PCV-10 in preventing invasivepneumococcal disease (IPD) and acute otitis media (AOM) in children ,5 years.

DATA SOURCES: Systematic searches of Medline, Embase, Cumulative Index to Nursing and Allied HealthLiterature, Web of Science, and Cochrane.

STUDY SELECTION: Eligible studies examined the direct effectiveness and/or efficacy of PCV-10 and PCV-13 inreducing the incidence of disease in healthy children ,5 years.

DATA EXTRACTION: Two reviewers independently conducted data extraction and methodologic qualityassessment.

RESULTS: Significant effectiveness against vaccine-type IPD in children#5 years was reported for$1 dose of PCV-13 in the 31 1 (86%–96%) and 21 1 schedule (67.2%–86%) and for PCV-10 for the 31 1 (72.8%–100%) and21 1 schedules (92%–97%). In children,12months of age, PCV-13 VE against serotype 19A post–primary serieswas significant for the 3 1 1 but not the 2 1 1 schedule. PCV-10 crossprotection against 19A was significant inchildren#5 years with$1 dose (82.2% and 71%). The majority of studies did not find either PCV to be effectiveagainst serotype-3. PCV-13 was effective against AOM (86%; 95% confidence interval [CI]: 61 to 94). PCV-10 waseffective against clinically defined (26.9%; 95% CI: 5.9 to 43.3) and bacteriologically confirmed AOM (43.3%; 95%CI: 1.7 to 67.3).

LIMITATIONS: Because of the large heterogeneity in studies, a meta-analysis for pooled estimates was not done.

CONCLUSIONS: Both PCVs afford protection against pneumococcal infections, with PCV-10 protecting against19A IPD, but this VE has not been verified in the youngest age groups.

aDepartment of Epidemiology, Biostatistics, and Occupational Health and bVaccine Study Centre, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec,Canada; cInfection Prevention and Control Unit, Department of Clinical Laboratory Medicine, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; dSt Francis XavierUniversity, Antigonish, Nova Scotia, Canada; and eDepartment of Microbiology, Infectious Diseases, and Immunology, University of Montreal, Montreal, Quebec, Canada

To cite: Berman-Rosa M, O’Donnell S, Barker M, et al. Efficacy and Effectiveness of the PCV-10 and PCV-13 Vaccines Against Invasive Pneumococcal Disease.Pediatrics. 2020;145(4):e20190377

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Streptococcus pneumoniae andHaemophilus influenzae arerecognized for their infectiouspotential in young children.1

Nontypeable Haemophilus influenzae(NTHi) strains, characterized by theirlack of a polysaccharide capsule, areassociated with noninvasive mucosaldiseases, such as acute otitis media(AOM) and sinusitis. Although notserious, AOM remains the leadingcause for antimicrobial prescriptionsin children in many countries,imposing a substantial burden onhealth care systems and potentiallyaccelerating the development ofantibiotic resistance.2

To reduce the burden of invasivepneumococcal disease (IPD) inchildren, the pneumococcal 7-valentconjugate vaccine (PCV-7), or Prevnar7, was licensed for use in Canada in20013 and implemented in infantvaccination programs across allprovinces and territories by 2006.4

Rapidly after implementation, theincrease in non–vaccine-type IPDassociated with serotype replacementthreatened to offset the gains offeredby the program.5 To address theproblem, higher-valent vaccines weredeveloped. The pneumococcal 10-valent conjugate vaccine (PCV-10), orSynflorix, became available in Canadain 2009, offering protection against 3additional serotypes: 1, 5A, and 7F4;it also employed a novel carrierprotein derived from NTHi presumedto grant protection against AOM andother diseases caused by NTHi.6

However, subjects vaccinated withPCV-10 showed a non-significantdecrease in NTHi carriage in the yearfollowing booster vaccination.7 In2010, pneumococcal 13-valentconjugate vaccine (PCV-13), orPrevnar13, was licensed, offeringprotection for PCV-10 serotypes with3 additional serotypes: 3, 6A, and19A.6 The inclusion of 19A, a serotypewith high invasive potential andassociated burden of disease, madethis vaccine particularly interesting8

and was selected for infant

immunization programs in mostjurisdictions.8

Despite their use in routine clinicalpractice, the comparativeeffectiveness of PCV-13 and PCV-10for the prevention of IPD and AOMhas yet to be assessed. Unlike PCV-7,for which efficacy was estimated fromrandomized controlled trials (RCTs),both PCV-10 and PCV-13 werelicensed on the basis of a noninferiorimmunologic response for the 7common serotypes found in PCV-7(4, 6B, 9V, 14, 18C, 19F, and 23F6).Authors of recent observationalstudies of vaccine effectiveness (VE)have suggested that PCV-10 mightafford crossprotection against thehighly pathogenic 19A serotype.9–11

The expected superior protection ofPCV-10 against AOM is howeverunclear.12

With nearly 7 years after theirworldwide implementation, there isan opportunity to assess theeffectiveness of PCV-10 and PCV-13to inform health policy discussionsconcerning pneumococcal infantimmunization programs. Wetherefore conducted a systematicreview of published studies in whichauthors evaluated the effectiveness ofPCV-10 and PCV-13 in providingprotection against IPD and AOM inchildren ages #5. We also evaluatedVE at reducing pneumococcalnasopharyngeal carriage (NPC).

METHODS

Search Strategy

In June of 2016, we systematicallysearched Ovid Medline(1946–present), Embase (Ovid), Webof Science, and Cumulative Index toNursing and Allied Health Literaturefor studies published between 2009and 2016 examining the effectivenessor efficacy of PCV-10 and PCV-13 forprotection against AOM and IPD inchildren. We combined free-textsearch terms for the concepts of “PCV-13” AND “PCV-10” and (“efficacy” OR

“effectiveness” OR “safety” OR “AOM”OR “IPD”). The search was updated inJuly of 2018. A sample of the fullsearch strategy is shown in detail inthe Supplemental Information.

Study Selection

Two researchers independentlyassessed the eligibility of each studyfor inclusion. Full texts of eligiblestudies were obtained and assessedindependently. A third reviewer wasconsulted when consensus could notbe reached.

Studies were eligible for inclusion ifthey examined the directeffectiveness or efficacy of PCV-10 orPCV-13 in preventing or reducing theincidence of IPD and/or AOM inhealthy children 5 years or younger.We included RCTs and cohort andcase-control studies as well assurveillance studies with individual-level data about vaccination status.Pre-post studies capturing both directand indirect VE were excluded. Werestricted inclusion to studies withconfirmed laboratory IPD diagnosis.For AOM, studies including diagnosisof AOM by diagnostic code, laboratoryresults, or clinical definitions werealso included. Studies were excludedif they were only available asabstracts from conferenceproceedings or published ina language other than English. Inaddition, studies that includedchildren who had received bothPCV-13 and PCV-10 in the analysisof VE, presented data exclusively onindividuals .5 years, or were specificto a subgroup of children withunderlying medical conditions wereexcluded. Country economic statuseswere based on rankings provided bythe World Bank Group’s WorldDevelopment Indicators13 on theyear(s) the study was conducted.13

Quality Assessment and DataExtraction

Two reviewers independentlyconducted data extraction andmethodologic quality assessment of

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https://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2019-0377/-/DCSupplemental/

included studies, using DistillerSR(Evidence Partners, Ottawa, Ontario,Canada). We extracted the country ofstudy, study time frame, fundingsource, study design, sample size,follow-up time, surveillance method,how outcomes were defined andascertained, vaccine assessed,comparator vaccine, vaccine schedule(2 1 1 or 3 1 1), method ofvaccination status ascertainment,and how VE was calculated. Forpopulation characteristics, weextracted vaccine coverage in theregion, whether the vaccine waspublicly or privately funded, the yearof pneumococcal vaccination programimplementation, and the ages atwhich vaccination was recommendedin the jurisdiction. For all studies, themain measure of interest was theeffect of the vaccine at reducing theprimary outcomes. For case-controland cohort studies, the relativemeasures were reported as oddsratios or incidence rate ratios. ForRCTs, the measure was the incidencerate ratio or the hazard ratio. TheVE was then calculated as VE =(1 2 relative measure) 3 100.

The outcomes extracted included VEand/or efficacy, effect measures andtheir confidence intervals (CIs), aswell as confounders for which themodel was adjusted. We focused onextracting VE against vaccine-typeinvasive pneumococcal disease (VT-IPD), vaccine-related IPD, serotypesunique to PCV-13 or PCV-10, andserotypes 19A and 3. For RCTs, onlyresults from intention-to-treatanalyses were extracted.

The risk of bias was evaluatedthrough the National AdvisoryCommittee on Immunizationguidelines for quality assessmentadapted from Harris et al,14 anadaptation of the methods employedby the US Preventive Task Force. Lackof control for age and/or underlyingmedical conditions15 as confounderswas considered a flaw that wouldrender a study as “fair.” Age wasconsidered a confounder because

younger children are at higher riskfor AOM and/or IPD because of theiranatomy and the immaturity of theirimmune system and may also bemore or less likely to be vaccinated,depending on public health strategies.Fatal flaws were determined a prioriand included inadequate selection ofcontrols for case-control studies andinadequate maintenance of balancedgroups for RCTs.

Data Analysis

We summarized all included studiesthrough descriptive analyses toprovide an overview of studies’characteristics, quality, and reportedoutcomes. Because of theheterogeneity in outcome assessmentand the various stratifications for VEmeasures across studies, a meta-analysis was not performed.Between-study heterogeneity wasevaluated by using visual assessmentof forest plots. We followed thePreferred Reporting Items forSystematic Reviews and Meta-Analysis.

RESULTS

Study Characteristics

Our initial search yielded a total of3073 studies (Fig 1). No furtherstudies were identified throughGoogle Scholar or hand searching ofrelevant articles. After removingduplicates, 1331 articles remainedand were screened by title andabstract. Of the 33 articles thatunderwent full-text screening, 12 metour inclusion criteria. Seven morearticles were added after the updatedsearch in 2018. When 2 studiesemployed the same data source, theearlier version was excluded.

From the 19 studies included (RCT =6; case-control = 12; cohort = 1),11 examined PCV-13 VE, with 1examining VE against AOM and NPCcompared to PCV-7, and the restexamined PCV-13 VE against IPDcompared with unvaccinatedchildren. Nine studies provided data

for PCV-10: 3 examined VE againstIPD compared to no pneumococcalvaccine; 2 examined VE against IPDwhen compared to either thehepatitis B vaccine or thediphtheria-tetanus-acellularpertussis–inactivated poliovirusHaemophilus influenzae typeb vaccine (DTaP-IPV/Hib), orInfanrixTM inactivated poliovirusH influenzae type b, with a hepatitis Avaccine and DTaP-IPV/Hib booster.The remaining 4 studies reported onPCV-10 efficacy against AOM ora proxy measure. For NPC, 2 studiesevaluated carriage after PCV-10administration and 1 evaluatedcarriage after PCV-13. There were nodirect comparisons of PCV-10 to PCV-13. Most studies were conducted incountries of high (n = 12) or upper-middle income status (n = 6), andonly 1 was conducted in a country oflower-middle status.16 The majorityof studies were rated as good (n =16), 3 were rated as fair, and nonewere rated as poor (Table 1).

VE Against IPD

In children ,5 years of age receivingat least 1 dose of PCV-13, VE againstVT-IPD was consistently high for the3 1 1 schedule17 (n = 4; range: 86%[95% CI: 74 to 93] to 96% [95% CI:43 to 100]) and 2 1 1 schedule (n =3; range: 67.2% [95% CI: 2.3 to 90] to86% [95% CI: 62 to 95]) (Table 2). Inthe same age group, when restrictingto IPD caused by serotypes unique toPCV-13, the estimate remainedpositive and significant(Supplemental Table 3). Only 1 studyreported a nonsignificant VE of PCV-13 against VT-IPD with the 2 1 1schedule among the subgroup ofchildren up to date with their vaccine(Table 2).

For PCV-10, VE against VT-IPD injurisdictions employing the 3 1 1schedule (n = 4; range: 72.8% [95%CI: 44.1 to 86.7] to 100% [95% CI: 83to 100]) or 2 1 1 schedule (n = 2;92% [95% CI: 58 to 100] and 97%[95% CI: 84 to 99]) was also reliably

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high among children ,5 years.Because no study was able toestimate PCV-10 VE against serotypesunique to its formulation, the VT-IPDestimates reflect VE against PCV-7serotypes. PCV-13 and PCV-10vaccine-type VE 6 their 95% CIs aredepicted in Fig 2 for comparison.

For the age subgroups with thehighest incidence of IPD (12 and24 months of age), effectivenessestimates were only provided forPCV-13. Against serotypes unique tothe 13-valent formulation, theeffectiveness post–primary series (ie,after the 2 or 3 priming doses butbefore the booster dose) in children,12 months of age hovered at ∼80%for both schedules (n = 2; 80% [95%CI: 46 to 93] and 80% [95% CI: 43 to93] for 3 1 1 and 2 1 1 schedule,respectively). Among children 12 and

24 months old, VE of the 2 1 1schedule against VT-IPD, althoughstatistically significant, was lowerthan the corresponding estimateobtained with the 3 1 1 vaccineschedule (Supplemental Table 3).

The question of PCV-10’scrossprotection was addressed in 3separate studies.10,18,19 Included inthese analyses were serotypes in thesame group as the vaccine-typeserotypes (ie, 6A, 6C, 6D, 7C, 9N,18A,18B, 19A, and 23A)10,18 or justserotypes 6A, 9N, and 19A.19 Forchildren ,5, Tregnaghi et al19

reported a nonsignificant vaccine-related VE of at least 1 dose of PCV-10 against serotypes 6A, 9N, or 19A(299.5%; 95% CI: 22100 to 81.9).For IPD caused by 6A, 6C, 6D, 7C,9N,18A, 18B, 19A, and 23A serotypes,PCV-10’s VE ranged from 64.8%

(95% CI: 15.3 to 85.4)18 to 77.9%(95% CI: 41.0 to 91.7)10 for childrenwho were up to date with theirvaccination status, whereas for atleast 1 dose, VE was 61.3%18

(95% CI: 14.5 to 82.5).

The VE for PCV-10 and PCV-13against IPD caused by serotypes19A or 3 could only be compareddescriptively for the age strataincluding all children ,5 yearsbecause this was the only strata forwhich both PCV-10 and PCV-13 hadVE estimates. Four studies16,17,20,21

reported on the VE of at least 1 doseof PCV-13 against 19A IPD offeringestimates ranging between 77%17

(95% CI: 47 to 90) and 85.6%21

(95% CI: 70.6 to 93.5) for the 3 1 1schedule and reduced but significantestimates for the 2 1 1 schedule(Table 2). For the 10-valentformulation, 1 study evaluated thecrossprotection against 19A IPDafforded by at least 1 dose of thevaccine in children #5 years11

(71.3%; 95% CI: 16.6 to 90.1).Although initially significant, thiscrosseffectiveness decreasedpostbooster (63.5%; 95% CI: 216.8to 88.6). In the same age group,Domingues et al11 reported a 19A VEof 82.2% (95% CI: 10.7 to 96.4) inthose who were up to date with thevaccine schedule at the time ofassessment (Supplemental Fig 3). Onestudy8 examined the 2 1 1 scheduleVE against 19A IPD for both PCV-10and PCV-13, offering comparableestimates of 74% (95% CI: 11 to 92)and 71% (95% CI: 24 to 89) for the13- and 10-valent formulations,respectively8 (Table 2).

For serotype 3, PCV-13 VE in children,12 months post–primary series wasnot statistically significant in eitherthe 3 1 1 schedule or 2 1 1schedule16,22 (Supplemental Table 3).The same trend was found for bothschedules after the booster dose forchildren ,5 years (Table 2). VEestimates against serotype 3 wereonly statistically significant whenconsidering all children ,5 years of

FIGURE 1Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram. Adapted fromMoher D, Liberati A, Tetzlaff J, Altman DG; the PRISMA Group. Preferred Reporting Items for Sys-tematic Reviews and Meta-Analyses: the PRISMA Statement. PLoS Med. 2009;6(7):e1000097.

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TABLE1Design

andMethodologicCharacteristicsof

Included

Studies

Study

Characteristics

Study

Palmu

etal26,a

Palmuet

al28,a

Palmuet

al27,a

Vesikari

etal25,a

Sáez-Llorens

etal24,a,b

Tregnaghi

etal19,a

Pichichero

etal23

Andrew

set

al22

Deceuninck

etal9

Cohenet

al29

Domínguez

etal32

Tomczyk

etal

40Domingues

etal11,d

Verani

etal18,d

VanderLinden

etal17

Weinberger

etal20

Moore

etal21

Guevaraet

al41

Suet

al16

Schedule

31

1/21

131

1/21

131

1/21

131

1/21

131

131

131

121

121

121

121

121

131

131

131

131

131

131

131

1

Type

RCT

RCT

RCT

RCT

RCT

RCT

Cohort

Case

control

Case

control

Case

control

Case

control

Case

control

Case

control

Case

control

Case

control

Case

control

Case

control

Case

control

Case

control

Design

Double-blind

cluster

RCT

(FinIP

trial)

Double-blind

clusterRCT

(FinIP

trial)

Double-blind

clusterRCT

(FinIP

trial)

Double-blind

cluster

RCT

(FinIP

trial)

Double-blind

RCT

(COM

PAS

trial)

Double-blind

RCT

(COM

PAS

trial)

Prospective

cohort

Indirect

cohort

Unmatched

Matched

Matched

Matched

Matched

Indirect

cohort

Indirect

cohort

Indirect

cohort

Matched

Matched

Matched

Country

Finland

Finland

Finland

Finland

Panama

Argentina,

Panama,

and

Columbia

USA

England,Wales,

and

Northern

Ireland

Quebec (Canada)

SouthAfrica

Barcelona

(Spain)

Dominican

Republic

Brazil

Brazil

Germ

any

Germ

any

USA

Navarra(Spain)

Taiwan

(China)

Econom

ic

status

High

High

High

High

UMUM

High

High

High

UMHigh

UMUM

UMHigh

High

High

High

LM

(2007–2009)/

UM

Jurisdiction

schedule

6–12

wk,4,

5,and

boosterat

11–12

mo/

6–12

wk,5

mo,and

boosterat

11–12

mo

6–12

wk,4,5,

andboosterat

11–12

mo/6–12

wk,5mo,and

boosterat

11–12

mo

6–12

wk,4,5,and

boosterat

11–12

mo/6–12

wk,5

mo,andbooster

at11–12

mo

6–12

wk,4,

5,and

boosterat

11–12

mo/

6–12

wk,5

mo,and

boosterat

11–12

mo

2,4,6,and

boosterat

15–18

mo

2,4,6,and

boosterat

15–18

mo

2,4,6,and

boosterat15

mo

2,4,and

boosterat

12

mo

2,4,and

boosterat

12

mo

6,14

wk,and

boosterat9mo

2,4,and

booster11–12

moc

2,4,and

boosterat

12

mo

2,4,6,and

boosterat

12

mo

2,4,6,and

boosterat

12

mo

2,3,4,and

boosterat

11–14

mo

2,3,4,and

boosterat

11–14

mo

2,4,6,and

boosterat

12–15

mo

2,4,6,and

boosterat

12–15

mo

Notspecified

Studyperiod

Feb

2009–Jan

2012

Feb2009–Dec

2011

Feb2009–Jan

2012

Feb

2009–Dec

2011

Aug2007–Jul

2011

Jun2007–Jul

2011

Sept

2010–Sept

2013

Apr2010–Oct

2013

Jan2005–NS

2013

Jan2012–Dec

2014

Jan2012–Jan

2016

Dec2013–Jan

2016

Mar

2010–Dec

2012

Mar

2010–Dec

2012

Jul2010–Jun

2013

Jan2010–Dec

2014

May

2010–April

2014

Jul2010–Dec

2014

Oct2007–Dec

2013

Meanlength

of

follow-up

(range)

25mo

(15–35)

24mo(14–34)

25mo(15–35)

18mo(NR)

31.4mo

(0–45)

AOM

31mo

(NR)

NRNA

NANA

NANA

NANA

NANA

NANA

NA

Vaccine

assessed

PCV-10

PCV-10

PCV-10

PCV-10

PCV-10

PCV-10

PCV-13

PCV-13

PCV-10

and

PCV-13

PCV-13

PCV-13

PCV-13

PCV-10

PCV-10

PCV-13

PCV-13

PCV-13

PCV-13

PCV-13

Comparator

HepatitisB

vaccine

HepatitisB

vaccine

HepatitisB

vaccine

HepatitisB

vaccine

HepatitisB

andDTaP-IPV/

Hib;

InfanrixTM

-

IPV/Hib

vaccines.

Booster:

hepatitisA

vaccineand

DTaP-IPV/Hib

HepatitisB

andDTaP-IPV/

Hib;

InfanrixTM

-

IPV/Hib

vaccines.

Booster:

hepatitisA

vaccineand

DTaP-IPV/Hib

PCV-7

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

No

pneumococcal

vaccine

Outcom

eIPDandNPC

Antim

icrobial

purchases

Tympanostom

y

tube

placem

ent

AOMandNPC

AOM

andNPC

IPDandAOM

AOM

and

NPC

IPD

IPD

IPD

IPD

IPD

IPD

IPD

IPD

IPD

IPD

IPD

IPD

NACI

quality

of

evidence

Good

Good

Good

Good

Good

Good

Good

Good

Good

Fair

Good

Good

Good

Good

Good

Good

Fair

Good

Fair

Note

theWorld

Bank

classifies

econom

iesinto

4incomegroupings(low

,low

ermiddle,uppermiddle,andhigh)on

thebasisof

thegrossnationalincomepercapita

ofagivenyear.Apr,April;Aug,August;COMPAS,Clinical

OtitisMedia

and

Pneumonia

Study;Dec,December;Feb,

February;FinIP,FinnishInvasive

Pneumococcaldiseasevaccine;INfanrixTM

-IPV/Hib,

inactivated

poliovirusHinfluenzae

type

b;Jan,

January;Jul,July;Jun,

June;LM

,lower

middle;

Mar,March;NA,not

applicable;N

ACI,NationalAdvisory

Committee

onImmunization;

NR,n

otreported;N

S,xxx;Oct,October;Sept,S

eptember;UM

,upper

middle;USA,UnitedStates

ofAm

erica.

aEstim

ateof

vaccineefficacy

asperstudy’s

design.

bPCV-10

coadministeredwith

DTaP-IPV/Hibvaccineat

2,4,and6mo.

cJurisdictionschedule

notreported

instudy.Retrievedfrom

http://www.analesdepediatria.org/en-immunisation-schedule-spanish-association-paediatrics-articulo-resumen-S2341287917301990.

dThese2studiesanalyzed

data

obtained

from

thesamestudy,using2different

methodologies:a

case-control

andan

indirect

cohort

design.


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TABLE 2 Reported VE for PCV-13 and PCV-10 Against IPD in Children#5 Years of Age, Stratified by Schedule (3 1 1 vs 2 1 1), Specific Serotypes Includedin Effectiveness Estimation, and the Number of Doses Received

Doses

$1 Dose $2Doses

Up to Date forAge

Post–PrimarySeries

Postbooster

PCV-13 IPD VE (95% CI); cases (if reported, vaccinated/unvaccinated): controls (if reported, vaccinated/unvaccinated) or No. discordant pairs (if reported,vaccinated/unvaccinated)VT-IPD3 1 1Van der Linden et al17 86 (74 to 93);

(25/55): (194/43)— — — —

Weinberger et al20 89 (76 to 95);(18/29): (99/18)

— 85a (64 to 94);(15/17): (90/15)

— —

Moore et al21 86b (75.5 to92.3); 102

— — — 90.4 (7.6 to 99); 4

Guevara et al41 96 (43 to 100);(2/6): (40/19)

— — — —

2 1 1Cohen et al29 — — — 85 (37 to 96); 11 —

Deceuninck et al9 86 (62 to 95);(10/71): (1478/

289)

— — — —

Domínguez et al32 75.8 (54.1 to87.2); (29/85):(189/298)

— — — —

Tomczyk et al40 67.2 (2.3 to 90);23:39

— 68.6 (229.6 to93.9); 17:39

— 78.8 (52.8 to 90.5) (15/71); (116/225) belongs to the Dominguez

study, not TomczykAndrews et al22 — — 75a (58 to 84); NA — —

19A3 1 1Van der Linden et al17 77 (47 to 90);

(14/17): (194/43)— — — —

Weinberger et al20 — — 83a (41 to 95);(6/6): (90/15)

— —

Moore et al21 85.6b (70.6 to93.5); 63

— — — —

Su et al16 82 (63 to 91); 12:267

— 89 (72 to 96); 7:215

— —

2 1 1Deceuninck et al29 74 (11 to 92);

(9/16): (1478/289)

— — 68c (213 to 91);(9/16): (1478/289)

—

Andrews et al9 — — 67a (33 to 84)(30/53): (280/76)

— —

Cohen et al32 — — — 94 (44 to 100); 3 —

Domínguez et al22 86 (51.2 to 99.7);(6/14): (35/50)

— — — 84.1 (297.1 to 98.7) (1/9): (14/29)

Serotype 33 1 1Van der Linden et a17 74 (2 to 93); 11:

237— — — —

Weinberger et al20 — — 0a (2791 to 89)7: 105

— —

Moore et al21 79.5d (30.3 to94.8); 16

— — — —

2 1 1Andrews et al22 — — 26a (269 to 68);

(21/28): (280/76)— —

Domínguez et al32 25.9 (265.3 to66.8); (22/37):

(91/140)

— — — 12.8 (2127.9 to 66.6); (12/27):(54/103)

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age who received at least 1 dose ofPCV-13 in the 31 1 schedule becausethe sample size was larger for thiscategory. These reported estimatesranged between 74%16 (95% CI: 2 to93) and 79.5%21 (95% CI: 30.3to 94.8).

VE Against AOM

The end points for the assessment ofVE against AOM were variable acrossstudies, thus limiting quantitative

comparisons between vaccines. Only1 study reported on PCV-13 VEagainst episodes of AOM.23 This wasa prospective cohort study comparingthe frequency of serotypes unique toPCV-13 in middle-ear fluid of childrenvaccinated in either a PCV-7 or PCV-

13 cohort. In children ,12 months ofage who had received the primaryseries of PCV-13, the estimated VE of

PCV-13 against AOM caused by the 6additional serotypes in PCV-13 was

86% (95% CI: 61 to 94) witha relative VE against 19A of 91%(95% CI: 58 to 97) and againstserotype 3–AOM of 15% (95% CI:2181 to 72).23

For PCV-10, VE was examinedthrough RCTs; thus, estimatesrepresent the vaccine’s efficacy. Forchildren ,12 months of age, 1study24 found a positive VE atpreventing at least 1 clinicallydefined AOM episode (26.9%; 95%

TABLE 2 Continued

Doses

$1 Dose $2Doses

Up to Date forAge

Post–PrimarySeries

Postbooster

PCV-10 IPD VE (95% CI); cases (if reported, vaccinated/unvaccinated): controls (if reported, vaccinated/unvaccinated) or No. discordant pairs (if reported,vaccinated/unvaccinated)VT-IPD3 1 1Palmu et al26 100 (83 to 100);

0: 12— — — —

Tregnaghi et al19 100 (77.3 to 100);0: 18

— — — —

Domingues et al11,e 81.9 (64.4 to90.8); 78: 147

— 83.8 (65.9 to92.3); 61: 147

95.4e (78.1 to99.0); 5: 108

—

Verani et al18,e 72.8 (44.1 to86.7); (61/147):

(78/94)

— 73.9 (41.9 to88.3); (32/147):

(40/94)

— —

2 1 1Palmu et al26 92 (58 to 100); 1:

12— — — —


289)

— — — —

19A3 1 1Verani et al18 71.3 (16.6 to

90.1); 15: 12— 63.4 (216.8 to

88.6); (12/26):(40/94)

— —

Domingues et al11 — — 82.2 (10.7 to96.4); 9: 26

— —

2 1 1 — — — — —


1478)

— — — —

Serotype 3 — — — — —

3 1 1 — — — — —

Domingues et al11 — — 7.8 (2271.9 to77.1) 99: 28

— —

PCV-13 includes serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F; PCV-10 includes serotypes: 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F. Children receiving 2 doses/3 doses injurisdictions with a 2 1 1/3 1 1 schedule were considered and are presented here under “Post–Primary Series.” Up to date for age indicates the VE for children who were up to datewith the vaccine given by their jurisdiction schedule at the time of assessment. Unique to PCV-13 refers to the serotypes unique to the PCV-13 formulation (1, 3, 6A, 7F, and 19A). —, notapplicable.a At least 2 doses before age 12 mo or 1 dose on or after age 12 mo.b Pneumococcal serotypes 6A, 9N, or 19A.c VE of $2 doses/ $3 in a jurisdiction with a 2 1 1/3 1 1 schedule is noted as postprimary.d Unadjusted VE estimates.e These 2 studies analyzed data obtained from the same study, using 2 different methodologies: a case-control and an indirect cohort design


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CI: 5.9 to 43.3) as well as for allepisodes of AOM (23.7%; 95% CI: 1.3to 41).24 The efficacy tended to falloff in older age groups (SupplementalTable 4). When the analysis wasrestricted to bacteriologicallyconfirmed AOM, the efficacyestimate in children ,12 monthsof age was significant whenconsidering the first episode (43.3%;95% CI: 1.7 to 67.3) but not forall AOM episodes (40.3%; 95% CI:24 to 65.7)24. Importantly,VE against NTHi AOM couldnot be demonstratedin children ,5 years of age whohad received at least 1 dose ofthe vaccine24 (SupplementalTable 4).

VE Against NPC

Pichichero et al23 examineddifferences in NPC in childrenvaccinated with PCV-7 or PCV-13.Post–primary series, PCV-13 resultedin reduced carriage of all 6 additionalserotypes included in its formulation(76%; 95% CI: 58 to 85), witha relative effectiveness of 73% (95%CI: 52 to 84) for reducing carriage ofserotype 19A.23 PCV-10 was noteffective at reducing vaccine-typecarriage when measured 1 monthafter the primary series of the 2 1 1

schedule (1.3%; 95% CI = 221.2 to19.8)25 but was at the other timepoints examined.24,25 For both the31 1 and 21 1 schedules, when NPCwas measured at either the 1- or 6-month post–primary series or at the3-month postbooster time point, PCV-10 VE at reducing NTHi carriage wasnot statistically significant.24,25

However, these studies saw lowcarriage levels in all groups across alltime points, resulting in wide CIs.

Quality Assessment

Sixteen of the 19 studies examinedmet all of Harris et al’s14 stipulatedcriteria for good internal validity. TheRCTs employed to assess PCV-10 VEhad balanced groups and ensuredmaintenance of randomization byreporting intention-to-treatresults.19,24,26–28 Although controlselection is always a challenge incase-control designs, most case-control studies matched on age andneighborhood of residence to reducethe bias in ascertainment of controls.Likewise, all but 3 case-controlstudies16,21,29 adjusted for underlyingmedical conditions when calculatingVE estimates (Table 1).

Indirect cohort studies circumventthe issue of control selection by

comparing VT-IPD cases tonon–vaccine-type IPD controls. Four

studies16,17,18,20 employed Broomeet al’s30 indirect cohort method for

VE calculation. In this method,differential serotype replacement in

vaccinated and unvaccinatedindividuals can introduce potential

bias and overestimate VE. Of the 4studies employing the indirect cohort

method for VE assessment, only 2acknowledged the potential biasintroduced by serotype

replacement.16,17 Weinberger et al20

and Verani et al18 did not measure the

potential effect of this bias; thus, the VEestimates may be overestimated. Threeof the included studies were rated asfair.16,21,29 One had several imbalancesbetween cases and controls, and thereported estimates were unadjusted forage or underlying medical conditions18;another did not adjust for underlyingcomorbidities, which was significantlydifferent between cases and theirmatched controls.29 Lastly, Su et al16 didnot adjust for underlying medicalconditions, and additionally, the studywas judged to have a significant risk ofnondifferential information biasbecause of the surveillance networkemployed to confirm vaccination status.

DISCUSSION

The higher-valent pneumococcalconjugate vaccines (PCVs) werelicensed on the basis of comparativeimmunogenicity to their precursorPCV-7. PCVs are among the mostexpensive vaccines currentlyavailable,31 and the question of theircomparative effectiveness remainshighly salient for public healthinitiatives worldwide. We identified19 studies examining the directVE of PCV-10 or PCV-13, but nonecompared the vaccines to each other.Differences in comparators,jurisdiction schedules, and thereported age group and/or dosingend points excluded the potential fora meta-analysis.

FIGURE 2Effectiveness of PCV-10 or PCV-13 against VT-IPD in children,5 years who received at least 1 dose ofthe vaccine.

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Across age groups, schedules, andnumber of doses, all studies reportedhigh and statistically significant VEagainst VT-IPD for both vaccines inchildren ,5 years of age. For PCV-10,no study was able to assess VEagainst serotypes unique to itsformulation (1, 5A, and 7F); thus, itsVE reflects PCV-7 VE. For serotype-specific effectiveness, all studiesstruggled with small numbers ofserotype-specific IPD cases.Regardless of schedule, most of theincluded studies that examined PCV-13 reported statistically significantprotection against IPD caused by the19A serotype for at least 1 dose in allchildren ,5 years.9,16,24,29–31

Importantly, for children ,12months, the 19A-IPD VEpost–primary series varied byschedule, with the 3 1 1 schedulegiving a statistically significant VEthat was not established in the2 1 1 schedule.17,22 Three studiesreported statistically significantcrossprotection of PCV-10 against19A IPD in all children ,5 years ofage receiving at least 1 dose and inthose being up to date with thevaccine given their age at the time ofassessment.8,10,18 Nevertheless,children ,2 years of age areespecially susceptible to IPD,33 andthe question of expandability of thecrossprotection to younger agegroups is pending on future studies.

PCV-10 effectiveness against serotype19A was observed in other studiesthat did not meet inclusion for thepresent review.10,34 A study in Chilereported a decrease in 19A-specificpneumococcal IPD, with 19A casesdecreasing from 13 to 8 from pre-to-post– PCV-10 introduction.34 InFinland, a population follow-up studycomparing a cohort of children whohad received PCV-10 toa nonvaccinated season-age matchedhistorical cohort reported a VEagainst serotype 19A of 62% (95%CI: 20 to 85).10 VE against 19A wasshown consistently for PCV-13,whereas the results varied for PCV-

10. Although PCV-10 was shown toinduce an increase in antibodyagainst serotype 19A after theprimary series, this increase wasconsistently lower than that observedin infants receiving PCV-13,regardless of schedule.29

For serotype-3, PCV-13 effectivenesswas observed only when all children,5 years who received at least 1 doseof vaccine were included in theanalysis. PCV-13 effectiveness againstAOM caused by serotype 3 in infants,12 months of age was limited. Theimmunogenicity of PCVs againstserotype 3 in infants was shown to berelatively low with no clear evidenceof toddler boosting by severaldifferent serotype-3 conjugatevaccines as measured by enzyme-linked immunosorbent assay.7,35–37

The question concerning which of thehigher-valent vaccines affordssuperior protection against AOM is ofinterest considering its high burdenin children.2,38 Of studies examiningPCV-10, most reported moderate tominimal direct protection againstAOM. As reported from the FinnishInvasive Pneumococcal diseasevaccine trial in Finland, estimates ofPCV-10 efficacy against AOMepisodes, or against tympanostomyprocedures or antimicrobialpurchases, were not significant.However, the authors emphasize thatby design, the trial wasunderpowered to detect anydifferences in these outcomes. TheLatin American Clinical Otitis Mediaand Pneumonia Study trial andresulting studies19,24 found positiveestimates for clinically and culture-confirmed AOM episodes. However,with regard to NTHi-linked AOM,PCV-10 efficacy was positive butnonsignificant. PCV-10 is currentlymarketed and sold under thepresumption that it affords superiorprotection against NTHi-associatedAOM.38 Yet, as observed in thisreview, this has yet to be objectivelyestablished.

Although the overall frequency ofAOM between cohorts vaccinatedwith PCV-7 and PCV-13 did notchange, the relative frequency of AOMcaused by the 6 additional Spneumoniae serotypes included inPCV-13 significantly decreased. Nodecrease in AOM caused by serotype3 was detected in this study.23 Aprospective study examined theeffects of PCV-7 and PCV-13sequential introduction on theincidence of pneumococcal-confirmedAOM. The authors reported a declineof 85% in the incidence of AOMcaused by the additional serotypesincluded in PCV-13.39 However, giventhe nature of the pre-post design, it isdifficult to untangle the direct effectsfrom the indirect protection affordedby years of PCV-7 administration.

In a previous systematic review, deOliveira et al31 examined the impactand effectiveness of the 13- and 10-valent vaccines on hospitalizationsand mortality due to IPD in children,5 years of age residing in LatinAmerican countries. Their studyincluded articles published in anylanguage and expanded the search toinclude the gray literature, including22 published and unpublishedstudies. As in the current review,none of the studies compared PCV-10to PCV-13, and meta-analysis was notpossible. For radiologically confirmedpneumonia, the all-serotypes VE ofPCV-13 in children ,12 months ofage ranged from 33% (95% CI: 25 to41) to 44.6% (95% CI: 24.6 to 59.3).For PCV-10, VE ranged from 13.6%(95% CI: 3 to 24.3) to 25.3% (95%CI: 24.6 to 26.1). For meningitishospitalizations and deaths, onlystudies examining PCV-10 met theinclusion criteria, giving a highvaccine-type VE in the 2 studiesreporting on this outcome (0–23months; VE = 77% [95% CI: 20 to94]; 2 to 49 months, VE = 87.7%[95% CI: 61.4 to 96.1]); for death dueto all serotypes, the estimatesprovided were high but had noassociated CIs.31 The authors


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concluded that with respect to theoutcomes examined, in children ,5years, there was no evidence to assertthe superiority of one vaccine overthe other.31 The review did not focuson serotype-specific PCVeffectiveness and did not differentiatebetween different vaccineschedules.31 Additionally, theinclusion of unpublished data andpre-post studies, although minimizingpublication bias, decreased theoverall quality of the evidenceanalyzed, a limitation that we tried toaddress in the current study.

We analyzed the evidence for directeffectiveness of the higher-valentpneumococcal vaccines frompublished studies worldwide. Wetried to maximize quality byrestricting inclusion to publishedstudies, which is reflected by thepreponderance of studies that wereassigned a “good” quality rating inanalyses of internal validity. Weprovided a thorough summary of allthe available evidence concerningserotype-specific VE, with a specificfocus on serotypes 19A and 3, whichremain contentious for PCV-10 andPCV-13, respectively.Notwithstanding these strengths, thepresent review has several potential

limitations. We restricted theinclusion to published articles andexcluded pre-post incidence studies.This may have discounted potentiallyrelevant results, particularly thosearising from developing economies.We further limited our inclusion tostudies published in English andexcluded the gray literature, whichincreases the potential for publicationbias. Finally, because of the largeheterogeneity in study design, endpoints, and age group and/or dosingstratification across studies, we wereunable to perform a meta-analysisand provide pooled estimates of VE.

CONCLUSIONS

Although the effectiveness againstVT-IPD was confirmed for bothvaccines, the comparative assessmentof PCV-10 and PCV-13 against AOMand serotypes 3 and 19A is precludedby the profound heterogeneity in thereported dose, age, and schedulecombinations across studies. PCV-13VE against 19A IPD was confirmed.Although PCV-10 seems to affordcrossprotection against 19A IPD, thequestion of whether the VE issufficiently effective in youngerchildren remains unanswered. Finally,

PCV-10’s superior protection againstAOM caused by NTHi is of publichealth importance but has to yet to beconfirmed in field studies of VE.

ABBREVIATIONS

AOM: acute otitis mediaCI: confidence intervalDTaP-IPV/Hib: diphtheria-tetanus-

acellular pertussis–inactivated poliovirusHaemophilusinfluenzae typeb vaccine

IPD: invasive pneumococcaldisease

NPC: nasopharyngeal carriageNTHi: nontypeable Haemophilus

influenzaePCV: pneumococcal conjugate

vaccinePCV-7: pneumococcal 7-valent

conjugate vaccinePCV-10: pneumococcal 10-valent

conjugate vaccinePCV-13: pneumococcal 13-valent

conjugate vaccineRCT: randomized controlled trialVE: vaccine effectivenessVT-IPD: vaccine-type invasive

pneumococcal disease

All authors contributed to the conception and design of the study, extracting, analyzing and interpretation of the data, and drafting the final manuscript, approved

the final manuscript as submitted, and agree to be accountable for all aspects of the work.

DOI: https://doi.org/10.1542/peds.2019-0377

Accepted for publication Dec 20, 2019

Address correspondence to Caroline Quach, MD, MSc, Centre Hospitalier Universitaire Sainte-Justine, 3175 Côte Sainte-Catherine, Office B.17.102, Montreal, QC,

Canada H3T 1C5. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2020 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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