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1HIGHLIGHTS OF PRESCRI BING INFORMATION
These highlights do not include all the information needed to use
PREVNAR 13 safely and effectively. See full prescribing information
for PREVNAR 13.
PREVNAR 13 (Pneumococcal 13 -valent Conjugate Vaccine
[Diphtheria CR M197Protein])
Suspension for intramuscular injection
Initial USApproval: 2010
--------------------------- INDICATIONS AND USAG E--------------------------
In children 6 weeks through 5 years of age (prior to the 6thbirthday),
Prevnar 13 is indicated for :
active immunization for the prevention of invasive disease caused by
Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14,
18C, 19A, 19F and 23F. (1.1)
active immunization for the prevention of otitis media caused by
S.pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No otitis
media efficacy data are available for serotypes 1, 3, 5, 6A, 7F, and
19A. (1 .1)
In children 6 years through 17 years of age ( prior to the 18thbirthday),
Prevnar 13 is indicated for:
active immunization for the prevention of invasive disease caused by S.
pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and
23F.(1.2)
In adults 18years of age and older, Prevnar 13 isindicated for:
active immunization for the prevention of pneumonia and invasive
disease caused by S.pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V,
14, 18C, 19A, 19F and 23F. (1.3)
Limitations of Prevnar 13 Useand Effectiveness
Prevnar 13 does not protect against disease caused by S. pneumoniae
serotypes that are not in the vaccine. (1.4)
------------------------ DOSAGE AND ADMINISTR ATION -------------------
Children 6 weeks through 5 years: The four -dose immunization series
consists of a 0.5 mL intramuscular injection administered at 2, 4, 6, and
12-15 months of age. (2.3)
Children 6 through 17 years of age: a single dose. (2.5)
Adults 18years and older: a single dose. (2.6)
------------------------ DOSAGE FORMS AND STR ENGTHS -----------------
0.5 mL suspension for intramuscular injection, supplied in a single -dose
prefilled syringe. (3)------------------------- CONTRAINDICATIONS ----------------------------------
Severe allergic reaction (e.g., anaphylaxis) to any component of Prevnar 13
or any diphtheria toxoid -containing vaccine. (4)
--------------------------- WARNINGS AND PRECAUT IONS ------------------
Apnea following intramuscular vaccination has been observed in some
infants born prematurely. Decisions about when to administer an
intramuscular vaccine, including Prevnar 13, to infants born prematurely
should be based on consideration of the individual infant’s medical status,
and the potential benefits and possible risk s of vaccination. (5. 3)
--------------------------- --ADVERSE REACTIONS ------------------------------
In infants and toddlers vaccinated at 2, 4, 6, and 12 -15 months of age in
USclinical trials, the most commonly reported solicited adverse
reactions (>5%) were irritability (>70%), injection site tenderness
(>50%), decreased appetite (>40%), decreased sleep (>40%), increased
sleep (>40%), fever (>20%), injection site redness (>20%), and
injection site swelling (>20%). (6.1)
In children aged 5 through 17 years, the most commonly reported
solicited adverse reacti ons (>5%) were injection site tenderness
(>80%), injection site redness (>30%), injection site swelling (>30%),
irritability (>20%), decreased appetite (>20%), increased sleep (>20%),
fever (>5%), and decreased sleep (>5%). (6.1)
In adults aged 18 years an d older ,the most commonly reported solicited
adverse reactions (>5%) were pain at the injection site (>50%), fatigue
(>30%), headache (>20%), muscle pain (> 20%), joint pain (>10%),
decreased appetite (>10%), injection site redness (>10%), injection site
swelling (>10%), limitation of arm movement (>10%), vomiting (>5%),
fever (>5%), chills (>5%) ,andrash (>5%). (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Wyeth
Pharmaceuticals LLC . at 1 -800-438- 1985 or VAERS at 1 -800-822-7967
or http://vaers.hhs.gov .
--------------------- USE IN SPECIFIC POPU LATIONS -----------------------
Pediatric Use: Safety and effectiveness of Prevnar 13 in children below the
age of 6 weeks have not been established. (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 7/2019
FDA-CBER-2021-5683-0951337
2FULL PRESCRIBING INFORMATION: CONTENTS*
1INDICATIONS AND USAG E
1.1 Children 6 Weeks Through 5 Years of Age
1.2Children 6 Years Through 17 Years of Age
1.3 Adults 18Years of Age and Older
1.4Limitations of Prevnar 13 Use and Effectiveness
2DOSAGE AND ADMINISTR ATION
2.1 Preparation for Administration
2.2 Administration Information
2.3Vaccination Schedule for Infants and Toddlers
2.4 Vaccination Schedule for Unvaccinated Children 7 Months
Through 5 years of Age
2.5Vaccination Schedule for Children 6 Years Through 17
Years of Age
2.6 Vaccin ationSchedule for Adults 18Years of Age and Older
3DOSAGE FORMS AND STR ENGTHS
4CONTRAINDICATIONS
5WARNINGS AND PRECAUT IONS
5.1Management of Allergic Reactions
5.2Altered Immunocompetence
5.3Apnea inPremature Infants
6ADVERSE REACTIONS
6.1 Clinical Trials Experience With Prevnar 13 in Children
6 week s Through 17 years of Age
6.2 Clinical Trials Experience With Prevnar 13 in Adults
≥18Years of Age
6.3 Post-marketing Experience With Prevnar 13 in Infants and
Toddlers7DRUG INTERACTIONS
7.1 Concomitant Immunizations
7.2 Immunosuppressive Therapies
7.3 Antipyretics
7.4 Prior Vaccination with PPSV23
8USE IN SPECIFIC POPU LATIONS
8.1 Pregnancy
8.2 Lactation
8.4Pediatric Use
8.5 Geriatric Use
8.6High Risk Populations
11DESCRIPTION
12CLINICAL PHARMACOLOG Y
12.1 Mechanism of Action
13NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14CLINICAL STUDIES
14.1 Efficacy Data
14.2 Prevnar 13 Clinical Trials in Childr en 6 Week s Through
17Years of Age
14.3 Prevnar 13 Immunogenicity Clinical Trials in Adults
14.4 Concomitant Vaccine Administration
15REFERENCES
16HOW SUPPLIED/STORAGE AND HANDLING
17PATIENT COUNSELING INFORMATION
*Sections or subsections omitted f rom the full prescribing information are not
listed
FDA-CBER-2021-5683-0951338
3FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Children 6 Weeks Through 5 Years of Age
In children 6 w eeks through 5 years of age(prior to the 6thbirthday ), Prevnar 13®is indicated
for:
active immunization for the prevention of invasive disease caused by Streptococcus
pneumoniae s erotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
active immunization for the prevention of otitis media caused b y S.pneumoniae
seroty pes 4, 6B , 9V, 14, 18C, 19F, and 23F. No otitis media efficacy data are available
for serot ypes 1, 3, 5, 6A, 7F, and 19A.
1.2 Children 6 Years Through 17 Years of Age
In children 6 years through 17 years of age (prior to the 18thbirthday ), Prevnar 13 is indicated
for:
active immunization for the prevention of invasive disease caused by S. pneumoniae
seroty pes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
1.3 Adults 18 Years of Age and Older
In adults 18 years of age and o lder, Prevnar 13 is indicated for:
active immunization f or the prevention of pneumonia and invasive disease caused b y
S.pneumoniae serot ypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
1.4 Limitations of Prevnar 13 Use and Effectiveness
Prevnar 13 does not protect agains t disease caused by S.pneumoniae seroty pes that are
not in the vaccine.
2 DOSAGE AND ADMINISTRATION
2.1 Preparation for Administration
Since this product is a suspension containing an adjuvant, shake vigorously immediatel y prior to
use to obtain a homo genous, white suspension in the vaccine container. Do not use the vaccine
if it cannot be resuspended. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration [see Description (11)] . This produ ct should not
be used if particulate matter or discoloration is found.
Do not mix Prevnar 13 with other vaccines/products in the same sy ringe.
FDA-CBER-2021-5683-0951339
42.2 Administration Information
For intramuscular injection only .
Each 0.5 mL dose is to be injected intramuscularly using a sterile needle attached to the
supplied prefilled s yringe . The preferred sites for injection are the anterolateral aspect of the
thigh in infants andthe deltoid muscle of the upper arm in toddlers, children and adults. The
vaccine should not be injected in the gluteal area or areas where there may be a major nerve
trunk and/or blood vessel.
2.3 Vaccination Schedule for Infants and Toddlers
Prevnar 13 is to be administered as a four -dose series at 2, 4, 6, and 12 -15 months of age .
Table 1: Vaccin ation Schedule for Infants and Toddlers
Dose Dose 1a,bDose 2bDose 3bDose 4c
Age at Dose 2 months 4 months 6 months 12-15 months
aDose 1 may be given as early as 6 weeks of age.
bThe recommended dosing interval is 4 to 8 weeks.
cThe fourth dose sho uld be administered at approximately 12 -15 months of age, and at least 2 months after the third dose.
2.4 Vaccination Schedule for Unvaccinated Children 7 Months Through 5 Years of
Age
For children 7 months through 5 years of age who have not received Prevnar®or Prevnar 13, the
catch -up schedule in Table 2 applies:
Table 2: Vaccination Schedule for Unvaccinated Children 7 Months of Age Through 5 Years of Age
Age at First Dose Total Number of 0.5 mL Doses
7-11 months of age 3a
12-23 months of age 2b
24 mon ths through 5 years of age (prior to the 6thbirthday) 1
aThe first 2 doses at least 4 weeks apart; third dose after the one -year birthday, separated from the second dose by at least 2 months .
bTwo doses at least 2 months apart.
The immune responses ind uced b y this catch -up schedule may result in lower antibody
concentrations for some seroty pes, compared to antibody concentratio ns following 4 doses of
Prevna r 13(given at 2, 4, 6, and 12 -15 months). In children 24 months through 5 years of age,
lower an tibody concentrations were observed for some serot ypes, compared to antibody
concentratio ns following 3doses of Prevna r 13(given at 2, 4, and 6 months).
2.5 Vaccination Schedule for Children 6 Years Through 17 Years of Age
In children 6 years through 17 years of age, Prevnar 13 is administered as single dose. If Prevnar
was previousl y administered, then at least 8 weeks should elapse before receiving Prevnar 13.
FDA-CBER-2021-5683-0951340
52.6 Vaccination Schedule for Adults 18 Y ears of Age and Older
Prevnar 13 is administered as asingle dose .
3 DOSAGE FORMS AND STRENGTHS
Prevnar 13 is a suspension for intramuscular injection available in 0.5 mL single -dose prefilled
syringes.
4 CONTRAINDICATIONS
Severe allergic reaction (e.g., anaph ylaxis) to an y component of Prevnar 13 or an y diphtheria
toxoid -containing vaccine [see Description (11) ].
5 WARNINGS AND PRECAUT IONS
5.1 Management of Allergic Reactions
Epinephrine and other appropriate agents used to manage immediate allergic reactions must be
immediately available should an acut eanaph ylactic reaction occur following administration of
Prevnar 13.
5.2 Altered Immunocompetence
Individuals with altered immunocompetence, including those at higher risk for invasive
pneumococcal disease (e.g., individuals with congenital or acquired spl enic dy sfunction, HIV
infection, malignancy , hematopo ietic stem cell transplant, nephrotic sy ndrome) ,may have
reduced antibody response sto immunization with Prevnar 13 [see Use in Specific Populations
(8.6)].
5.3 Apnea in Premature Infants
Apnea followi ng intramuscular vaccination has been observed in some infants born
prematurel y. Decisions about when to administer an intramusc ular vaccine, including
Prevnar 13, to infants born prematurel y should be based on consideration of the individual
infant’s medi cal status and the potential benefits and possible risks of vaccination.
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely vary ing conditions, adverse -reaction rates
observed in the clinical trials of a vaccine cannot be directl y comp ared to rates in the clinical
trials of another vaccine and may not reflect the rates observed in practice.
FDA-CBER-2021-5683-0951341
66.1 Clinical Trials Experience With Prevnar 13 inChildren 6 Weeks Through
17Years of Age
The safet y of Prevnar 13 was eval uated in 13 clinical tr ials in which 4,729 infants (6 weeks
through 11 months of age) and toddlers (12 months through 15 months of age) received at
least one dose of Prevnar 13 and 2,760 infants and toddlers received at least one dose of
Prevnar active control. Safet y data for t he first three doses are available for all 13 infant
studies; dose 4 data are available for 10 studies; and data for the 6 -month follow -up are
available for 7 studies. The vaccination schedule and concomitant vaccinations used in these
infant trials were c onsistent with countr y-specific recommendations and local clinical practice.
There were no substantive differences in demographic characteristics between the vaccine
groups. By race, 84.0% of subjects were White, 6.0% were Black or African -American, 5.8%
were Asian and 3.8% were of ‘Other’race (most of these being biracial). Overall, 52.3% of
subjects were male infants.
Three studies in the US (Studies 1, 2 and 3)1,2,3evaluated the safet y of Prevnar 13 when
administered concomitantly with routine US pediat ric vaccinations at 2, 4, 6, and 12 -15months
of age. Solicite d local and sy stemic adverse reactions were recorded dail y by parents/guardians
using an electronic diary for 7 consecutiv e day s following each vaccination. For unsolicited
adverse events, stud ysubjects were monitored from administration of the first dose until one
month after the infant series, and for one month after the administration of the toddler dose.
Information regarding unsolicited and serious adverse events, newl y diagnosed chronic m edical
conditions, and hospitalizations since the last visit were collected during the clinic visit for the
fourth- study dose and during a scripted telephone interview 6 months after the fourth -study
dose. Serious adverse events were also collected through out the study period .Overall, the safet y
data show a simil ar proportion of Prevnar 13 and Prevnar subjects reporting serious adverse
events. Among US study subjects, a similar proportion of Prevnar 13 and Prevnar recipients
reported solicited local and sy stemic adverse reactions as well as unsolicited adverse events.
Serious Adverse Events in All Infant and Toddler Clinical Studies
Serious adverse events were collected throughout the study period for all 13 clinical trials. This
reporting period is longer t han the 30- day post -vaccination period used in some vaccine trials.
The longer reporting period may have resulted in serious adverse events being reported in a
higher percentage of subjects than for other vaccines. Serious adverse events reported followin g
vaccination in infants and toddlers occurred in 8.2% among Pre vnar 13 recipients and 7.2 %
among Prevnar recipients. Serious adverse events observed during diff erent study periods for
Prevnar 13 and Prevnar respectivel y were: 1) 3.7% and 3.5% from dose 1 to the blood draw
approximately 1 month after the infant series; 2) 3.6% and 2.7% from the blood draw after the
infant series to the toddler dose; 3) 0.9% and 0.8% from the toddler dose to the blood draw
approximately 1month after the toddler dose and 4) 2.5% and 2.8% during the 6 month
follow -up period after the last dose.
Themost common ly reported serious adverse events were in the ‘Infections and infestations’
system organ class including bronchiolitis (0.9%, 1.1%), gastroenteritis, (0.9%, 0.9%), and
pneumonia (0.9%, 0.5%) for Prevnar 13 and Prevnar respectivel y.
FDA-CBER-2021-5683-0951342
7There were 3 (0.063 %) deaths among Prevnar 13 recipients, and 1 (0.036%) death in Prevnar
recipients, all as a result of sudden infant death syndrome ( SIDS). These SIDS rates are
consistent wi th published age specific background rates of SIDS from the year 2000 .
Among 6,839 subjects who received at least 1 dose of Prevnar 13 in clinical trials conducted
globally, there was 1 h ypotonic -hyporesponsive episode adverse reaction reported (0.015%).
Among 4,204 subjects who received at least 1 dose of Prevnar in clinical trials conducted
globall y, there were 3 h ypotonic -hyporesponsive episode adverse reactions reported (0.071%).
All 4 events occurred in a single clinical trial in Brazil in which subje cts received whole cell
pertussis vaccine at the same time as Prevnar 13 or Prevnar.
Solicited Adverse Reactions in the Three USInfant and Toddler Studies
A total of 1,907 subjects received at least 1 dose of Prevnar 13 and 701 subjects received at least
1dose of Prevnar in the three US studies (Studies 1, 2 and 3)1,2,3. Most subjects were White
(77.3 %), 14.2% were Black o rAfrican- American, and 1.7% were Asi an; 79.1 % of subjects
were non -Hispanic and non -Latino and 14.6% were Hispanic or Latino. Overall, 53.6 % of
subjects were male infants.
The incidence and severity of solicited adverse reactions that occurred within 7 da ys following
each dose of Prevnar 13 or Prevnar administered to US infants and toddlers are shown in
Tables 3and 4.
FDA-CBER-2021-5683-0951343
8Table 3: Percentage of USInfant and Toddler Subjects Reporting Solicited Local Reactions at the Prevnar 13 or Prevnar Injection Sites
With in 7 Days After Each Vaccination at 2, 4, 6, and 12 -15 Months of Agea
Dose 1 Dose 2 Dose 3 Dose 4
Graded Local
ReactionPrevnar 13
(Nb=1375 -
1612)
%Prevnar
(Nb=516 -
606)
%Prevnar 13
(Nb=1069 -
1331)
%Prevnar
(Nb=405 -
510)
%Prevnar 13
(Nb=998 -
1206)
%Prev nar
(Nb=348 -
446)
%Prevnar 13
(Nb=874 -
1060)
%Prevnar
(Nb=283 -
379)
%
Rednessc
Any 24.3 26.0 33.3 29.7 37.1 36.6 42.3 45.5
Mild 23.1 25.2 31.9 28.7 35.3 35.3 39.5 42.7
Moderate 2.2 1.5 2.7 2.2 4.6 5.1 9.6 13.4d
Severe 0 0 0 0 0 0 0 0
Swellingc
Any 20.1 20.7 25.2 22.5 26.8 28.4 31.6 36.0d
Mild 17.2 18.7 23.8 20.5 25.2 27.5 29.4 33.8
Moderate 4.9 3.9 3.7 4.9 3.8 5.8 8.3 11.2d
Severe 0 0 0.1 0 0 0 0 0
Tenderness
Any 62.5 64.5 64.7 62.9 59.2 60.8 57.8 62.5
Interferes with
limbmovement10.4 9.6 9.0 10.5 8.4 9.0 6.9 5.7
aData are from three primary USsafety studies (the USPhase 2infant study [National Clinical Trial (NCT) number NCT 00205803 ]Study
1,the US noninferiority study [NCT 00373958 ]Study 2 ,and the USlot consist ency study [NCT00444457 ]Study 3 ).All infants received
concomitant routine infant immunizations. Concomitant vaccines and pneumococcal conjugate vaccines were administered in diffe rent
limbs.
b Number of subjects reporting Yes for at least 1 day or No fo rall days.
cDiameters were measured in caliper units of whole numbers from 1 to 14 or 14+. One caliper unit = 0.5 cm. Measurements were r ounded
up tothe nearest whole number. I ntensity of induration and erythema were then characterized as Mild (0.5 -2.0cm), Moderate (2.5 -7.0cm),
or Severe (>7.0 cm ).
d Statistically significant difference p <0.05. No adjustments for multiplicity.
FDA-CBER-2021-5683-0951344
9Table 4: Percentage of USInfant and Toddler Subjects Reporting Solicited Systemic Adverse Reactions Within 7 Days After Eac h
Vaccination at 2, 4, 6, and 12 -15 Months of Agea,b
Dose 1 Dose 2 Dose 3 Dose 4
Graded
Systemic
EventsPrevnar 13
(Na=1360 -
1707)
%Prevnar
(Na=497 -
640)
%Prevnar 13
(Na=1084 -
1469)
%Prevnar
(Na=409 -
555)
%Prevnar 13
(Na=997 -
1361)
%Prevnar
(Na=354 -
521)
%Prevnar 13
(Na=850 -
1227)
%Prevnar
(Na=278 -
436)
%
Feverc
Any 24.3 22.1 36.5 32.8 30.3 31.6 31.9 30.6
Mild 23.6 21.7 34.9 31.6 29.1 30.2 30.3 30.0
Moderate 1.1 0.6 3.4 2.8 4.2 3.3 4.4 4.6
Severe 0.1 0.2 0.1 0.3 0.1 0.7 1.0 0
Decreased
appetite48.3 43.6 47.8 43.6 47.6 47.6 51.0 49.4
Irritability 85.6 83.6 84.8 80.4 79.8 80.8 80.4 77.8
Increased sleep 71.5 71.5 66.6 63.4 57.7 55.2 48.7 55.1
Decreased
sleep42.5 40.6 45.6 43.7 46.5 47.7 45.3 40.3
aNumber of subjects reporting Yes for at least 1 day or No for all days.
b Data arefrom three primary US safety studies (the US Phase 2infant study [NCT00205803 ]Study 1 ,the US noninferiority study
[NCT 00373958 ]Study 2 ,and the US lot consistency study [NCT 00444457 ]Study 3 ). All infants received concomitant routine infant
immunizations. Concomitant vaccines and pneumococcal conjugate vaccines were administered in different limbs.
cFever gradings: Mild ( ≥38oC but ≤39oC), Moderate (>39oC but ≤40oC), and Severe (> 40oC). No other systemic e vent other than fever
was graded. Parents reported the use of antipyretic medication to treat or prevent symptoms in 62 to 75% of subjects after an y of the 4
doses. There were no statistical differences in frequencies of adverse reactions reported between the Prevnar 13 and Prevnar groups .
The incidence rates of any fever ( ≥38.0°C) were similar on day s 1 and 2 following each dose of
Prevnar 13 compared to after each dose of Prevnar administered to US infants and toddlers
(day 1 = day of vaccination). After dose 1, fever was reported in 11.0- 12.7% on day 1 and
6.4-6.8% on day 2. After dose 2, fever was reported in 12.3 -13.1% on day 1 and 12.5- 12.8% on
day 2. After dose 3, fever was reported in 8.0 -9.6% on day 1 and 9.1- 10.5% on day 2. And after
dose 4, fever was reported in 6.3- 6.4% on day 1 and 7 .3-9.7% on day 2.
Unsolicited Adverse Reactions in the Three US Infant and Toddler Safety Studies
The following were determined to be adverse drug reactions based on experience with
Prevnar 13 in clinical trials .
Reactions occurring in greater than 1% of i nfants and toddlers: diarrhea, vomiting, and rash.
Reactions occurring in less than 1% of infants and toddlers : crying, hy persensitivity reaction
(including face edema, dy spnea, and bronchospasm), seizures (including febrile seizures), and
urticaria or urt icaria -like rash.
FDA-CBER-2021-5683-0951345
10Safety Assessments in the Catch -Up Studies in Infants and Children Through 5 Years of
Age
In a catch- up study4conducted in Poland (Study 4), 354 children (7 months through 5 years of
age) rec eiving at least one dose of Prevnar 13 were also monitored for safety . All subjects in this
study were W hite and non-Hispanic. Overall, 49.6% of subjects were male infants. The
incidence and severity of solicited adverse reactions that occurred within 4 da ys following each
dose of Prevnar 13 administered to pneumococcal-vaccine naïve children 7 months through
5years of age are shown in Tables 5 and 6.
Table 5: Percentage of Subjects 7 Months Through 5 Years of Age Reporting Solicited Local Reactions Within 4 Days After
Each Catch -Up Prevnar 13 Vaccinationa
7 through 11 months 12 through 23 months 24 months through 5
years
Graded Local Reaction Dose 1
Nb=86
%Dose 2
Nb=86-87
%Dose 3
Nb=78-82
%Dose 1
Nb=108 -110
%Dose 2
Nb=98-106
%Dose 1
Nb=147 -149
%
Rednessc
Any 48.8 46.0 37.8 70.0 54.7 50.0
Mild 41.9 40.2 31.3 55.5 44.7 37.4
Moderate 16.3 9.3 12.5 38.2 25.5 25.7
Severe 0.0 0.0 0.0 0.0 0.0 0.0
Swellingc
Any 36.0 32.2 25.0 44.5 41.0 36.9
Mild 32.6 28.7 20.5 36.7 36.2 28.2
Moderate 11.6 14.0 11.3 24.8 12.1 20.3
Severe 0.0 0.0 0.0 0.0 0.0 0.0
Tenderness
Any 15.1 15.1 15.2 33.3 43.7 42.3
Interferes with limb
movement1.2 3.5 6.4 0.0 4.1 4.1
a Study conducted in Poland (NCT 0045245 2)Study 4 .
b Number of subjects reporting Yes for at least 1 day or No for all days.
cDiameters were measured in caliper units of whole numbers from 1 to 14 or 14+. One caliper unit = 0.5 cm. Measurements were
rounded up to the nearest whole number . Intensity of redness and swelling were then characterized as Mild (0.5 -2.0 cm), Moderate
(2.5-7.0 cm), or Severe (>7.0 cm ).
FDA-CBER-2021-5683-0951346
11Table 6: Percentage of Subjects 7 Months Through 5 Years of Age Reporting Solicited Systemic
Adverse Reactions Within 4 Days After E ach Catch -Up Prevnar 13 Vaccinationa
7 through 11 months 12 through 23 months 24 months through
5years
Systemic Reaction Dose 1
Nb=86-87
% Dose 2
Nb=86-87
%Dose 3
Nb=78-81
%Dose 1
Nb=108
% Dose 2
Nb=98-100
% Dose 1
Nb=147 -148
%
Feverc
Mild 3.4 8.1 5.1 3.7 5.1 0.7
Moderate 1.2 2.3 1.3 0.9 0.0 0.7
Severe 0.0 0.0 0.0 0.0 0.0 0.0
Decreased appetite 19.5 17.2 17.5 22.2 25.5 16.3
Irritability 24.1 34.5 24.7 30.6 34.0 14.3
Increased sleep 9.2 9.3 2.6 13.0 10.1 11.6
Decreased sleep 24.1 18.4 15.0 19.4 20.4 6.8
a Study conducted in Poland (NCT 00452452 )Study 4 .
b Number of subjects reporting Yes for at least 1 day or No for all days.
c Fever gradings: Mild ( ≥38oC but ≤39oC), Moderate (>39oC but ≤40oC), and Severe (>40oC). No other systemic event other than fever
was graded .
A US study5(Study 5) evaluated the use of Prevnar 13 in children pre viously immunized with
Prevnar. In this open label trial, 596health y children 15 through 59 months of age pr eviously
vaccinated with at least 3 doses of Prevnar, received 1 or 2 doses of Prevnar 13. Children
15months through 23 months of age (group 1) received 2 doses, and children 24 months
through 59 months of age ( group 2) received one dose. Most subjects were White ( 74.3%),
14.9% were Black or African -American, and 1.2% were Asi an; 89.3% of subjects were
non-Hispanic and non -Latino and 10.7% were Hispanic or Latino. Overall, 52.2% of subjects
were male.
The incidence and severity of solicited adverse reactions that occurred within 7 day s following
one dose of Prevnar 13 administered to children 15 months through 59 months of age are shown
in Tables 7 a nd 8.
FDA-CBER-2021-5683-0951347
12Table 7: Percentage of Subjects 15 Months Through 59 Months of Age, Previously Vaccinated With3 or 4
Prior Infant Doses of Prevnar, Reporting Solicited Local Reactions Within 7 Days After One
Supplemental Prevnar 13Vaccinationa
15 months thro ugh 23 monthsb24 months through 59 monthsc
Graded Local Reaction1dose Prevnar 13
3prior Prevnar doses
Nd=67-72
% 1dose Prevnar 13
4prior Prevnar doses
Nd=154-184
% 1dose Prevnar 13
3or 4 prior Prevnar doses
Nd=209-238
%
Rednesse
Any 26.4 28.2 35.4
Mild 18.8 24.3 31.1
Moderate 11.4 7.5 12.1
Severe 1.5 0.0 0.0
Swellinge
Any 23.9 19.6 20.7
Mild 18.6 16.4 17.2
Moderate 8.8 8.1 7.5
Severe 0.0 0.0 0.0
Tenderness
Any 48.6 47.3 62.6
Interferes with limb
movement5.9 6.4 10.7
a Study conducted in US NCT00761631 (Study 5) .
bDose 2 data not shown.
cThe data for this age group are only represented as a single result as 95% of children received 4 doses of Prevnar prior to e nrollment.
dNumber of subjects reporting Yes for at least 1 d ay or No for all days.
eDiameters were measured in caliper units of whole numbers from 1 to 14 or 14+. One caliper unit = 0.5 cm. Measurements were
rounded up to the nearest whole number. Intensity of redness and swelling were then characterized as Mild (0.5 -2.0cm), Moderate
(2.5-7.0 cm), or Severe (>7.0 cm).
Table 8: Percentage of Subjects 15 Months Through 59 Months of Age, Previously Vaccinated With3 or 4
Prior Infant Prevnar Doses, Reporting Solicited Systemic Adverse Reactions Within 7 Days Afte r One
Supplemental Prevnar 13 Vaccinationa
15 through 23 monthsb24 months through 59monthsc
Systemic
Reaction1dose Prevnar 13
3prior Prevnar doses
Nd=66-75
%1dose Prevnar 13
4prior Prevnar doses
Nd=154-189
%1dose Prevnar 13
3or4prior Prev nardoses
Nd=209-236
%
Fevere
Any 19.1 19.9 8.1
Mild 16.2 17.4 7.6
Moderate 6.1 3.9 1.9
Severe 0.0 0.0 0.5
Decreased appetite 44.4 39.3 28.1
Irritability 73.3 65.1 45.8
Increased sleep 35.2 35.3 18.8
Decreased sleep 25.0 29.7 14.8
a Study conducted in US NCT00761631 (Study 5) .
bDose 2 data not shown.
cThe data for this age group are only represented as a single result as 95% of children received 4 doses of Prevnar prior to e nrollment.
dNumber of subjects reporting Yes for at least 1 day or No for all days.
eFever gradings: Mild ( ≥38oCbut ≤39oC), Moderate (> 39oCbut ≤40oC), and Severe (> 40oC). No other systemic event other than fever
was graded.
FDA-CBER-2021-5683-0951348
13Clinical Trials Experience With Prevnar 13 in Children 5 Through 17 Years of Age
In a US study5(Study 5), the safet y of Prevnar 13 was evaluated in children 5 through 9 years of
age previousl y immunized with at least one dose of Prevnar, and in children 10 through 17 years
of age with no prior pneu mococcal vaccination. In this open label trial, 592 children , including
those with asthma, received a single dose of Prevnar 13. The percentage of children 5 through
9years of age who received 3 and 4 prior doses of Prevnar was 29.1% and 54.5% respectivel y.
Most subjects were White ( 72.8%), 21.8% were Bl ack or African -American, and 1.5% were
Asian; 91.4% of subjects were non -Hispanic and non -Latino and 8.6% were H ispanic or Latino.
Overall, 51.2% of subjects were male.
The incidence and severity of solici ted adverse reactions that occurred within 7 day s following
one dose of Prevnar 13 administered to children 5 through 17 years of age are shown in Tables 9
and 10.
Table 9: Percentage of Subjects 5 Through 17 Years of Age, Reporting Solicited Local Reactio ns Within
7 Days After Prevnar 13Vaccinationa
Vaccine Group (as Administered)
Prevnar 13
(5 Through 9 Years)Prevnar 13
(10 Through 17 Years)
Local Reaction Nbnc% Nbnc%
Redness
Any 233 100 42.9 232 70 30.2
Mildd226 63 27.9 226 48 21.2
Moderated218 48 22.0 221 31 14.0
Severed212 7 3.3 213 4 1.9
Swelling
Any 226 85 37.6 233 86 36.9
Mildd220 48 21.8 221 50 22.6
Moderated219 48 21.9 226 48 21.2
Severed211 7 3.3 214 4 1.9
Tenderness
Any 265 230 86.8 283 252 89.0
Significante221 43 19.5 242 106 43.8
a Study conducted in US NCT00761631 (Study 5) .
bN = number of subjects reporting Yes for at least 1 day or No for all days.
cn = Numbe r of subjects reporting the specific characteristic.
dMild, 0.5 –2.0 cm; moderate, 2.5 –7.0 cm; severe, >7.0 cm .
eSignificant = present and interfered with limb movement.
FDA-CBER-2021-5683-0951349
14Table 10: Percentage of Subjects 5 Through 17 Years of Age, Reporting Solicited Systemic Adverse Reactions Within 7 Days After
Prevnar 13 Vaccinationa
Vaccine Group (as Administered)
Prevnar 13
(5 Through 9 Years)Prevnar 13
(10 Through 17 Years)
Systemic Event Nbnc% Nbnc%
Any fever ≥38 C 214 13 6.1 214 12 5.6
Mildd212 9 4.2 214 11 5.1
Moderated212 5 2.4 212 1 0.5
Severed210 1 0.5 212 1 0.5
Decreased appetite 227 52 22.9 223 51 22.9
Irritability 234 73 31.2 234 59 25.2
Increased sleep 226 48 21.2 229 61 26.6
Decreased sleep 212 12 5.7 224 42 18.8
Hives (urticari a) 213 4 1.9 214 3 1.4
aStudy conducted in US NCT00761631 (Study 5).
bN = number of subjects reporting Yes for at least 1 day or No for all days.
cn = Number of subjects reporting the event.
dFever grad ings: Mild ( ≥38oC but ≤39oC), Moderate (>39oC but ≤40oC), and Severe (>40oC). No other systemic event other than fever
was graded. Parents reported the use of antipyretic medication to treat or prevent symptoms in 45.1% and 33.1% of subjects 5 through 9
years of age and 10 through 17 years of age, respectively.
6.2 Clinical Trials Experience With Prevna r13 in Adults ≥18 Years of Age
The safet y of Prevnar 13 was assessed in 7 clinical studies (Studies 6-12)6-12conducted in the
US and Europe which included 91,593 adults (48,806 received Prevnar 13) ranging in age from
18 through 101 years.
The 48,806 Prevnar 13 recipients included 899 adults who were aged 18 throug h 49 years,
2,616 adults who were aged 50 through 64 years, 45,291 adults aged 65 years and older. Of the
48,806 Prevnar 13 recipients, 46,890 adults had not previously received Pneumovax®23
(pneumococcal pol ysaccharide vaccine [23 -valent], PPSV23) (“PPSV 23 unvaccinated”) and
1,916 adults were previously vaccinated (“PPSV23 previously vaccinated”) with PPSV23 at least
3years prior to enrollment.
Safety and Immunogenicity Studies
Safety and immunogenicity of Prevnar 13 is supported by 6 clinical studies. Study 66evaluated
the safet y and immunogenicity of Prevnar 13 in adults 18 through 64 y ears of age who had not
received a previous dose of pneumococcal vaccine. Adults 18 through 59 years of age received a
single dose of Prevnar 13, and adults 60 through 6 4 years of age received a single dose of
Prevnar 13 or PPSV23.
Study 7 was randomized and compared the safet y and immunogenicit y of Prevnar 13 with
PPSV23 as a single dose in adults ≥70 y ears vaccinated with PPSV23 (≥5 years prior to
enrollment).7Study 8 was randomized and evaluated the safety and immunogenicity of Prevnar
13 and PPSV23 in different sequential order in PPSV23 naive adults aged 60 through 64 years8.
One clinical safet y study9(Study 9) of Prevnar 13, conducted in PPSV23 previously vacci nated
(≥3 years prior to enrollment) adults aged ≥68 y ears was a single arm study . Two studies, one in
the US10(Study 10) in adults aged 50 through 59 years and the other in Europe11(Study 11) in
adults aged ≥65 y ears, evaluated the concomitant administr ation of Prevnar 13 with inactivated
FDA-CBER-2021-5683-0951350
15influenza vaccine, trivalent (Fluarix®, A/H1N1, A/H3N2, and B, Fall 2007/Spring 2008: IIV3) in
these two age groups in PPSV23 unvaccinated adults.
The total safet y population in the 6 safet y and immunogenicit y studies was 7,097. I n 5 of the
6safet y and immunogenicity studies, more females than males were enrolled (50.2% - 61.8%).
Across the 6 studies the racial distribution included: >85% White; 0.2% -10.7% Black or African
American; 0% -1.7% Asian; <1% Native Hawaiian or other Pacific Islander; ≤1%, American
Indian or Alaskan Native. Ethnicity data were not collected in Study 11; in the 5 other studies
0.6%- 4.8% were Hispanic or Latino.
In five studies,6-8,10,11subjects with pre -existing underly ing diseases were enroll ed if the medical
condition was stable (did not require a change in therap y or hospitalization for worsening disease
for 12 weeks before receipt of study vaccine) except in Study 9 where subjects were enrolled if
the medical condition was stable for 6 or more weeks before receipt of study vaccine.
In the 6 safet y and immunogenicity studies,6-11subjects were excluded from study participation
due to prior receipt of diphtheria toxoid -containing vaccines within 6 months of study vaccine.
However, the time o f prior receipt of a diphtheria toxoid -containing vaccine was not recorded.
Solicited adverse reactions for Prevnar 13 in the safet y and immunogenicity studies were
monitored by subjects recording local adverse reactions and sy stemic reactions daily using an
electronic diary for 14 consecutive day s following vaccination. Unsolicited serious and
non-serious adverse events were collected for one month after each vaccination. I n addition,
serious adverse events were collected for an additional 5 months a ftereach vaccination (at the
6-month follow -up phone contact) in all studies except Study 11.
Following licensure of Prevnar 13 in adults ≥50 y ears of age, a randomized, double -blind,
placebo- controlled US study (Study 13) was conducted to evaluate concomitan t administration
of Prevnar 13 with inactivated influenza vaccine, quadrivalent (Fluzone® Quadrivalent , A/H1N1,
A/H3N2, B/Brisbane, and B/Massachusetts, Fall 2014/Spring 2015: IIV4) in PPSV23 previously
vaccinated adults ≥50 y ears of age. Unsolicited serio us and non- serious adverse events were
collected as described above for Studies 6-10 .
Efficacy Study
Study 1212was a randomized double -blind placebo- controlled study conducted in the
Netherlands in community -dwelling adults aged 65 y ears and older with n o prior pneumococcal
vaccination history . A total of 84,496 subjects received either a single dose of Prevnar 13
(42,240) or placebo (42,256) in a 1:1 randomization. Among the 84,496 subjects, 58,072 (68.7%)
were ≥65 to <75 years of age, 23,481 (27.8%) wer e ≥75 and <85 years of age, and 2,943 (3.5%)
were ≥85years of age. In the total safet y population, more males (55.9%) were enrolled than
females. The racial distribution was 98.5% White, 0.3% Black, 0.7% Asian, 0.5% Other, with
<0.1% having missing data.
Adults with immunocompromising conditions or receiving immunosuppressive therapy and
adults residing in a long- term care facility or requiring semiskilled nursing care were excluded.
FDA-CBER-2021-5683-0951351
16Adults with pre -existing medical conditions ,as well as subjects with a history of smoking were
eligible for enrollment. In the safet y population, 42.3% of subjects had pre -existing medical
conditions including heart disease (25.4%), lun g disease or asthma (15.1%) and ty pe 1 and t ype 2
diabetes mellitus (12.5%). Smoking was reported at baseline b y 12.3% of the subjects .
Fora subset of 2,011 subjects (1,006 Prevnar 13 recipients and 1, 005 placebo recipients) ,
solicited adverse reactions were monitored b y recording local and s ystemic events using
electronic diaries for 7 day s after vaccination; unsolicited adverse events were collected for
28days after vaccination, and serious adverse events were collected for 6 months after
vaccination. For the remaining 41,23 1 Prevnar 13 and 41,250 placebo vaccinated subjects,
serious adverse events were collected for 28 day s after vaccination.
Serious Adverse Events in Adult Clinical Studies
Safety and Immunogenicity Studies
Across the 6 safet y and immu nogenicit y studies ,6-11serious adverse events within 1 month of
vaccination were reported after an initial study dose in 0.2% -1.4% of 5 ,057subjects vaccinated
with Prevnar 13,and in 0. 4%-1.7% of 1 ,124 subjects vaccinated after an initial study dose of
PPSV23. From 1 month to 6 months after an initial study dose, serious adverse events were
reported in 0.2%- 5.8% of subjects vaccinated during the studies with Prevnar 13 and in 2.4 %-
5.5% of subjects vaccinated with PPSV23. One case of ery thema multiforme oc curred 34 day s
after receipt of a second dose of Prevnar 13.
Twelve of 5,667 (0.21%) Prevnar 13 recipients and 4 of 1,391 ( 0.29 %)PPSV23 recipients died.
Deaths occ urred between Day 3and Day 309 after study vaccination with Prevnar 13or
PPSV23 . Two of 12 deaths occurred within 30 days of vaccination and b oth deaths were in
subjects > 65years of age .One death due to cardiac failure occurred 3 day s after receiving
placebo. This subject had received Prevnar 13 and IIV3 one month earlier. T he other death w as
due to peritonitis 20 day s after receiving Prevnar 13. The repor ted causes of the 10 remaining
deaths occurring greater than 30 day s after receiving Prevnar 1 3 were cardiac disorders ( 4),
neoplasms (4), Mycobacterium avium complex pulmonary infection (1)andseptic shock (1).
Efficacy Study
In Stud y 1212(subjects 65 y ears and older), serious adverse events within 1 month of vaccination
were reported in 327 of 42,237 (0.8%) Prevnar 13 recipients (352 events) and in 314of
42,225 (0.7%) placebo recipien ts(337 events) . In the subset of subjects where serious adverse
events were monitored for 6 months, 70of 1,006 (7%) Prevnar 13 vaccinated subjects
(90events) and 60of 1,005 (6%) placebo vaccinated subjects (69 events) reported serious
adverse events.
During the follow -upperiod (average of 4 y ears) for case accumulation there were 3,006 deaths
(7.1%) in the Prevnar 13 group and 3 ,005 deaths (7.1%) in the placebo group . There were
10deaths ( <0.1%) in the Prevnar 13 group and 10 deaths ( <0.1%) in the pl acebo group within
28days of vaccination. There were 161deaths ( 0.4%) in the Prevnar 13 group and 144 deaths
FDA-CBER-2021-5683-0951352
17(0.3%)in the placebo group within 29 days –6 months following vaccination. These data do not
provide evidence for a causal relationship between deaths and vaccination with Prevnar 13.
Solicited Adverse Reactions in Adult Clinical Studies
The incidence and severity of solicited adverse reactions that occurred within 7 or 14days
following each dose of Prevnar 13,PPSV23 ,or placebo administered to adults in 5studies are
shown in Tables 11, 12, 13,and 14.
The commonly reported local adverse reactions after Prevnar 13 vaccination in PPSV23
unvaccinated and PPSV23 previously vaccinated adults were redness, swelling and pain at the
injection site, or limitation of arm movement (Tables 11and 12).The commonly reported
systemic adverse reactions in PPSV23 unvaccinated and PPSV23 previously vaccinated adults
were fatigue, headache, chills, rash, decreased appetite, or muscle pain and joint pain (Tables 13
and 14).
FDA-CBER-2021-5683-0951353
18Table 11 -Percentage of Subjects With Solicited Local Adverse Reactions Within 7 or 14 Days in PPSV23 Unvaccinated Adultsa
Study 6 Study 8 Study 12
Age in
Years 18-49 50-59 60-64 60-64 ≥65
Local
ReactionPrevnar 13b
Nc=266- 787
%Prevnar 13b
Nc=152 -322
%Prevnar 13
Nc=193 -331
%PPSV23
Nc=190 -301
%Prevnar 13
Nc=270 -370
%PPSV23
Nc=134 -175
%Prevnar 13
Nc=886 -914
%Placebo
Nc=859 -865
%
Rednessd
Any 30.5 15.8 20.2 14.2 12.2 11.2 4.9g1.2
Mild 26.4 15.2 15.9 11.2 8.3 9.7 3.7g0.8
Moderate 11.9 5.0 8.6 4.9 6.4 3.9 1.7g0.3
Severe 2.8 0.7 1.7 0.0 1.2 0.8 0.5 0.1
Swellingd
Any 39.4 21.7 19.3 13.1 10.0 10.4 6.8g1.2
Mild 37.2 20.6 15.6 10.1 8.2 6.1 5.5g0.7
Moderate 15.1 4.3 8.2 4.4 3.8 7.6 2.6g0.6
Severe 1.4 0.0 0.6 1.1 0.0 0.0 0.1 0.1
Paine
Any 96.7 88.8 80.1 73.4 69.2g58.3 36.1g6.1
Mild 93.2 85.9 78.6g68.6 66.1g52.9 32.9g5.6
Moderate 77.1 39.5 23.3 30.0 20.1 21.7 7.7g0.6
Severe 16.0 3.6 1.7 8.6g2.3 0.8 0.3 0.1
Limitation
of arm
movementf
Any 75.2 40.7 28.5 30.8 23.5 28.2 14.1g3.2
Mild 71.5 38.6 26.9 29.3 22.7 26.1 12.4g2.5
Moderate 18.5 2.9 2.2 3.8 1.2 3.1 1.7g0.5
Severe 15.6 2.9 1.7 4.3 1.1 2.3 1.2 0.7
a Studies conducted in US NCT00427895 (Study 6) and NCT00574548 (Study 8) reported local reactions within 14 days. Study conducted in the
Netherlands NCT00744263 (Study 12) reported local reactions within 7 days.
bOpen label administration of Prevnar 13.
cNumber of subjects with known values (number of subjects reporting yes for at least one day or no for all days) .
dDiameters were measured in caliper units of whole numbers from 1 to 21 or 21+. One calip er unit = 0.5 cm. Measurements were rounded up to
the nearest whole number. I ntensity of redness and swelling were then characterized as Mild = 2.5 to 5.0 cm, Moderate = 5.1 t o 10.0 cm, and
Severe is >10.0 cm.
eMild = awareness of symptom but easily toler ated, Moderate = discomfort enough to cause interference with usual activity, Severe =
incapacitating with inability to do usual activity.
fMild = some limitation of arm movement, Moderate = unable to move arm above head but able to move arm above shoulde r, and Severe = unable
to move arm above shoulder.
g Statistically significant difference p <0.05. No adjustments for multiplicity.
FDA-CBER-2021-5683-0951354
19Table 12-Percentage of Subjects With Solicited Local Adverse Reactions in PPSV23 Previously Vaccinated Adultsa
Study 7 Study 9
Age in Years ≥70 ≥68
Local ReactionPrevnar 13
Nc=306 -362
%PPSV23
Nc=324 -383
%Prevnar 13b
Nc=664 -777
%
Rednessd
Any 10.8 22.2g14.3
Mild 9.5 13.5 12.6
Moderate 4.7 11.5g6.5
Severe 1.7 4.8g1.1
Swell ingd
Any 10.4 23.1g12.8
Mild 8.9 14.0g10.9
Moderate 4.0 13.6g5.5
Severe 0.0 4.8g0.6
Paine
Any 51.7 58.5 51.0
Mild 50.1 54.1 49.4
Moderate 7.5 23.6g9.0
Severe 1.3 2.3 0.2
Limitation of arm movementf
Any 10.5 27.6g16.2
Mild 10.3 25.2g14.8
Moderate 0.3 2.6g1.6
Severe 0.7 3.0g1.6
a Study conducted in US and Sweden NCT00546572 (Study 7) reported local reactions within 14 days . Study conducted in US, Sweden and
Germany NCT00500266 (Study 9) reported local reactions within 14 days .
bOpen label administration of Prevnar 13.
cNumber of subjects with known values .
dDiameters were measured in caliper units of whole numbers from 1 t o 21 or 21+. One caliper unit = 0.5 cm. Measurements were rounded
up to the nearest whole number. I ntensity of redness and swelling were then characterized as Mild = 2.5 to 5.0 cm, Moderate = 5.1 to 10.0
cm, and Severe is >10.0 cm.
eMild = awareness of sy mptom but easily tolerated, Moderate = discomfort enough to cause interference with usual activity, Severe =
incapacitating with inability to do usual activity.
fMild = some limitation of arm movement, Moderate = unable to move arm above head but able to move arm above shoulder, and Severe =
unable to move arm above shoulder .
g Statistically significant difference p <0.05. No adjustments for multiplicity.
FDA-CBER-2021-5683-0951355
20Table 13 - Percentage of Subjects With Solicited Systemic Events in PPSV23 Unvaccinated Adultsa
Study 6 Study 8 Study 12
Age in
Years18-49 50- 59 60-64 60-64 ≥65
Prevnar 13b
Nc=221-561
%Prevnar 13b
Nc=137 -248
%Prevnar 13
Nc=174 -277
%PPSV23
Nc=176 -273
%Prevnar 13
Nc=261 -328
%PPSV23
Nc=127 -173
%Prevnar 13
Nc=881 -896
%Placebo
Nc=860-878
%
Systemic
Event
Fever
≥38.0 C 7.2 1.5 4.0 1.1 4.2 1.6 2.9d1.3
38.0 Cto
38.4 C4.21.5 4.0 1.1 3.8 0.81.1 0.6
38.5 Cto
38.9 C1.90.0 0.6 0.0 0.8 0.00.6 0.2
39.0 Cto
40.0 C1.40.0 0.0 0.0 0.4 0.80.7 0.2
>40.0 Ce0.5 0.0 0.0 0.0 0.0 0.0 0.8 0.3
Fatigue 80.5 63.3 63.2 61.5 50.5 49.1 18.8d14.8
Headache 81.4 65.9 54.0 54.4 49.7 46.1 15.9 14.8
Chills 38.1 19.6 23.5 24.1 19.9 26.9 9.4 8.4
Rash 21.3 14.2 16.5 13.0 8.6 13.4 3.3d0.8
Vomiting 15.0 6.9 3.9 5.4 3.1 3.1 0.3 0.9
Decreased
appetite55.625.3 21.3 21.7 14.7 23.0d 5.33.7
Generalized
new muscle
pain82.0
61.8 56.2 57.8 46.9 51.5 18.4d8.4
Generalized
aggravated
muscle pain55.9
39.9 32.6 37.3 22.0 32.5d9.1d4.4
Generalized
new joint
pain41.7
31.5 24.4 30.1 15.5 23.8d7.4 5.4
Generalized
aggravated
joint pain28.6
25.6 24.9 21.4 14.0 21.1 5.2 4.2
a Studies conducted in US NCT00427895 (Study 6) and NCT00574548 (Study 8) reported systemic events within 14 days. Study conducted in
the Netherlands NCT00744263 (Study 12) reported systemic events within 7 days.
bOpen label administration of Prevnar 13.
cNumber of subjects with known values (number of subjects reporting yes for at least one day or no for all days) .
d Statistically significant difference p <0.05 . No adjustments for multiplicity.
e Fevers >40.0 Cwere confirmed to be data entry errors and remain in the table for the following: 1 case in the 18 -to 49 -year-old cohort (Study 6),
and 7 cases in the Prevnar 13 group and 3 cases in placebo group (Stud y 12). For the other cohorts in Study 6 and for Study 8, data entry errors
were removed.
FDA-CBER-2021-5683-0951356
21Table 14-Percentage of Subjects With Systemic Events in PPSV23 Previously Vaccinated Adultsa
Study 7 Study 9
Age in Years ≥70 ≥68
Prevnar 13
Nc=299 -350
%PPSV23
Nc=303- 367
%Prevnar 13b
Nc=635- 733
%
Systemic Event
Fever
≥38.0 C 1.0 2.3 1.1
38.0 C to38.4 C 1.0 2.0 0.8
38.5 C to38.9 C 0.0 0.0 0.0
39.0 Cto40.0 C 0.0 0.3 0.3
>40.0 C 0.0 0.0 0.0
Fatigue 34.0 43.3d34.4
Headache 23.7 26.0 26.1
Chills 7.9 11.2 7.5
Rash 7.3 16.4d8.4
Vomiting 1.7 1.3 0.9
Decreased appetite 10.4 11.5 11.2
Generalized new muscle pain 36.8 44.7d25.3
Generalized aggravated muscle
pain20.6 27.5d12.3
Generalized new joint pain 12.6 14.9 12.8
Generalized aggravated joint
pain11.6 16.5 9.7
aStudy conducted in US and Sweden NCT00546572 (Study 7) reported systemic events within 14 days. Study conducted in US, Sweden and
Germany NCT00500266 (Study 9) reported systemic events within 14 days .
bOpen label administration of Prevnar 13.
cNumber of subjects with known values.
dStatistically significant difference p <0.05. No adjustments for multiplicity.
Safety Results from Adult Clinical Stud yof Concomi tant Administration of Prevnar 13
and IIV4 (Fluzone Quadrivalent )(Study 13)
The safet y profile of Prevnar 13 when administered concomitantl y with seasonal inactivated
influenza vaccine , quadrivalent ,to PPSV23 previously vaccinated adults ≥50 y ears of ag e was
generall y consistent with the known safet y profile of Prevnar 13.
6.3 Post-marketing Experience With Prevnar 13 in Infants and Toddlers
The following adverse events have been reported through passive surveillance since market
introduction of Prevnar 13.Because these events are reported voluntaril y from a population of
uncertain size, it is not alway s possible to reliabl y estimate their frequency or establish a causal
relationship to the vaccine. The following adverse events were included based on one or more of
the following factors: severity , frequency of reporting, or strength of evidence for a causal
relationship to Prevnar 13 vaccine.
Administration site conditions : Vaccination- site dermatitis, vaccination -site pruritus,
vaccination -site urticaria
Blood and l ymphatic sy stem disorders : Lymphadenopathy localized to the region of the
injection site
Cardiac disorders : Cyanosis
FDA-CBER-2021-5683-0951357
22Immune s ystem disorders : Anaphy lactic/anaph ylactoid reaction including shock
Nervous system disorders : Hypotonia
Skin and subcutaneous tissue disorders: Angioneurotic edema, ery thema multiforme
Respiratory : Apnea
Vascular disorders : Pallor
7 DRUG INTERACTIONS
7.1 Concomitant Immunizations
In clinical trials with infants and toddlers , Prevnar 13 was administered concomitantly with the
following US -licensed vaccines: Pediarix [Diphtheria and Tetanus Toxoids and Acellular
Pertussis Adsorbed, Hepatitis B (Recombinant) and I nactivated Poliovirus Vaccine Combined]
(DTaP -HBV -IPV) and ActHIB [Haemophilus b Conjugat e Vaccine (Tetanus Toxoid
Conjugate)] (PRP -T) for the first three doses and with PedvaxHI B [Haemophilus b Conjugate
Vaccine (Meningococcal Protein Conjugate)] (PRP -OMP), M -M-R II [Measles, Mumps,
Rubella Virus Vaccine Live] (MMR) and Varivax [Varicella Vir us Vaccine L ive], or ProQuad
[Measles, Mumps, Rubella and Varicella Virus Vaccine Live] (MMRV) and VAQTA [Hepatitis
A vaccine, Inactivated] (HepA) for dose 4 [see Clinical Studies (14.2) and Adverse Reactions
(6.1) ].
In children and adolescents, data are i nsufficient to assess the concomitant administration of
Prevnar 13 with Human Papillomavirus Vaccine (HPV), Meningococcal Conjugate Vaccine
(MCV4) and Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine,
Adsorbed (Tdap).
In adults, Pr evnar 13 was administered concomitantly with US-licensed inactivated influenza
vaccine s, trivalent and quadrivalent ( Studies10, 11 and 13) [see Clinical Studies (14. 4) and
Adverse Reactions (6.2) ].There are no data on the concomitant administration of Pre vnar 13
with diphtheria toxoid -containing vaccin es and other vaccines licensed for use in adults 50 y ears
of age and older.
When Prevnar 13 is administered at the same time as another injectable vaccine(s), the vaccines
should alway s be administered with d ifferent s yringes and given at different injection sites.
Do not mix Prevnar 13 with other vaccines/products in the same sy ringe.
7.2 Immunosuppressive Therapies
Individuals with impaired immune responsiveness due to the use of immunosuppressive therapy
(including irradiation, corticosteroids, antimetabolites, alky lating agents, and cy totoxic agents)
may not respond optimally to active immunization.
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237.3 Antipyretics
A post -marketing clinical study conducted in Poland using a non -US vaccination schedule ( 2, 3,
4, and 12 months of age) evaluated the impact of prophy lactic oral acetaminophen on antibody
responses to Prevnar 13. The data show that 3 doses of acetaminophen (the first dose
administered at the time of each vaccination and the subsequent doses at 6 to 8 hour intervals)
reduced the antibod y response to some serot ypes following the third dose of Prevnar 13,
compared with responses among infants who received antipy retics onl y as needed for treatment.
Reduced antibody responses were not observed after the fourth dose of Prevnar 13 when
acetaminophen was administered proph ylactically .
7.4 Prior Vaccination with PPSV23
Prior receipt of PPSV23 within 1 y ear results in diminished immune responses to Prevnar 13
compared to PPSV23 naïve individuals [see Cli nical Studies (14.3) ].
8 USE IN SPECIFIC POPU LATIONS
8.1 Pregnancy
Risk Summary
All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general
population, the estimated background risk of major birth defects and miscarriag e in clinicall y
recognized pregnancies is 2% to 4% and 15% to 20%, respectively . Available data on Prevnar
13 administered to pregnant women are insufficient to inform vaccine -associated risks in
pregnancy .
A developmental toxicity study has been performed in female rabbits administered Prevnar 13
prior to mating and during gestation. Each dose was approximately 20 times the human dose.
This study revealed no evidence of harm to the fetus due to Prevnar 13 ( see 8.1 Data ).
Data
Animal
In a developmental to xicity study , female rabbits were administered Prevnar 13 b y
intramuscular injection twice prior to mating (17 day s and 3 day s prior to mating) and twice
during gestation (gestation day s 10 and 24) , 0.5 mL/rabbit/occasion (each dose approximately
20 times the human dose). No adverse effects on pre -weaning development were observed.
There were no vaccine -related fetal malformations or variations.
8.2 Lactation
Risk Summary
Data are not available to assess the effects of Prevnar 13 on the breastfed infant or on milk
production/excretion. The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for Prevnar 13 and an y potential adverse
effects on the breastfed child from Prevnar 13 or from the underl ying m aternal condition. For
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24preventive vaccines, the underly ing maternal condition is susceptibility to disease prevented by
the vaccine.
8.4 Pediatric Use
Safety and effectiveness of Prevnar 13 in children below the age of 6 weeks have not been
established.
8.5 Geriatric Use
Of the total number of Prevnar 13 recipients aged 50 years and older in clinical studies
(N=47,907), 94.5%(45,2 91of 47,907 ) were 65 years and older and 30.3 % (14,498 of 47,907)
were 75 years and older [see Clinical Studies (14.1) and ( 14.3) ].
8.6 High Risk P opulations
Individuals with the diseases or conditions listed below are at increased risk of pneumococcal
disease. Immunogenicit y and safet y data in these populations are limited.
Infants Born Prematurely
Immune responses elicited by Prevnar 13 administered on a US schedule to preterm infants have
not been studied. When preterm infants (<37 weeks gestational age, N=100) were administered
4 doses of Prevnar 13 on a non- US schedule, the seroty pe-specific IgG antibody responses after
the third and fourth dose were lower compared to responses among term infants (≥37 weeks
gestational age, N=100) for some serot ypes; the effectiveness of Prevnar 13 in preterm infants
cannot be established from this study .
Children with Sickle Cell Disease
In an open -label, single -arm, descriptive study , 2 doses of Prevnar 13 were administered
6months apart to children ≥6 to <18 y ears of age with sickle cell disease who previously
received PPSV23 at least 6 months prior to enrollment. Children with a prior history of
pneumococcal conjugate vaccination were excluded. For all vaccine serot ypes,
anti-pneumococcal opsonophagocy tic activity (OPA) geometric mean antibody titers (GMTs)
were higher after the first dose compared to pre -vaccination (N=95 -131); OPA GMTs following
the first and second dose were comparable. The effectiveness of Prevnar 13 in this specific
population has not been established.
Individuals with Hematopoietic Stem Cell Transplant
In an open -label, single -arm, descriptive study , 4 doses of Prevnar 13 were administered to
subjects ≥2 years of age (ra nge 2 to 71 years) who had received an allogeneic hematopoietic stem
cell transplant 3 to 6 months prior to enrollment. All subjects had a history of stable engraftment
(absolute neutrophil count>1000/µL , platelet count >50,000/µL ), and did not have uncontrolled
graft versus host disease. The first three doses of Prevnar 13 were administered one month apart,
followed b y a fourth dose of Prevnar 13 six months after the third dose. Sera were obtained
approximately one month after each vaccination .Immune responses (IgG GMCs) after the first
FDA-CBER-2021-5683-0951360
25dose of Prevnar 13 were numericall y higher for all seroty pes compared with baseline. In addition,
after each subsequent dose of Prevnar 13, IgG GMCs for all serot ypes were numerically higher
than responses after the previous dose. A post hoc anal ysis of the immune responses as measured
by OPA antibody assay showed the pattern of functional antibody responses to be consistent with
IgG responses for each seroty pe. The effectiveness of Prevnar 13 in this specific population has
not been established.
Individuals with HIV Infection
In an open -label, single -arm, descriptive study, 3 doses of Prevnar 13 were administered
6months apart to HIV -infected adults ≥18 y ears of age (median age 48 y ears), with CD4 counts
≥200 cells/µL and serum HIV RNA titer <50,000 copies/mL . All subjects had been vaccinated
previously with PPSV23 at least 6 months prior to enrollment. For all vaccine serot ypes anti -
pneumococcal OPA GMTs were numericall y higher after the first dose compared to
pre-vaccination (N=227 -253); OPA GMTs following the first, second and third dose were
generall y comparable .The effectiveness of Prevnar 13 in this specific population has not been
established.
In an open -label, single -arm, descriptive study , 3 doses of Prevnar 13 were administered 1 month
apart to HIV -infected subjects ≥6 years of age with CD4 count s ≥200 cells/ μL, and serum HIV
RNA titer <50,000 copies/mL . Subjects had not previously been vacci nated with a pneumococcal
vaccine. For all vaccine seroty pes anti -pneumococcal OPA GMTs were numericall yhigher after
the first dose compared to pre- vaccination (N=197 -257); OPA GMTs following the first, second
and third dose were generally comparable. The effectiveness of Prevnar 13 in this specific
population has not been established.
11 DESCRIPTION
Prevnar 13, Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM 197 Protein) is a sterile
suspension of saccharides of the capsular antigens of Streptococ cus pneumoniae serot ypes 1, 3,
4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, individually linked to non -toxic diphtheria
CRM 197protein. Each seroty pe is grown in so y peptone broth. The individual polysaccharides
are purified through centrifugation, pr ecipitation, ultrafiltration, and column chromatography .
The poly saccharides are chemicall y activated to make saccharides, which are directl y
conjugated b y reductive amination to the protein carrier CRM 197, to form the gl ycoconjugate.
CRM 197is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium
diphtheriae strain C7 (β197) grown in a casamino acids and yeast extract -based medium or in a
chemicall y-defined medium . CRM 197is purified through ultrafiltration, ammonium sulfate
precipitation, and ion -exchange chromatography . The individual gl ycoconjugates are purified
by ultrafiltration and column chromatography and anal yzed for saccharide to protein ratios,
molecular size, fre e saccharide, and free protein.
The individual gl ycoconjugates are compounded to formulate Prevnar 13. Potency of the
formulated vaccine is determined b y quantification of each of the saccharide antigens and b y the
saccharide to protein ratios in the individual gly coconjugates. Each 0.5 mL dose of the vaccine
isformulated to contain approximately 2.2 μg of each of Streptococcus pneumoniae serot ypes 1,
3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F saccharides, 4.4 μg of 6B saccharides, 34μg
FDA-CBER-2021-5683-0951361
26CRM 197 carrier protein, 100 μg polysorbate 80, 295 μg succinate buffer and 125 μg aluminum as
aluminum phosphate adjuvant .
The tip cap and rubber plunger of the prefilled s yringeare no t made with natural rubber latex .
12 CLINICAL PHARMACOLOG Y
12.1 M echanism of A ction
Prevnar 13, comprised of pneumococcal polysaccharides conjug ated to a carrier protein
(CRM 197), elicits a T -celldependent immune response .Protein carrier -specific T -cells provide
the signals needed for maturation of the B -cell response .
Nonclinical and clinical data support opsonophagocy tic activity , as measured by
opsonophagocy tic activity (OPA) antibody assay , as a contributor to protection against
pneumococcal disease. The OPA antibody assay provides an in vitro measurement of the ability
of serum antibodies to eliminate pneumococci by promoting complement -mediated
phagocy tosis and is believed to reflect relevant in vivo mechanisms of protection against
pneumococcal disease. OPA antibody titers are expressed as the reciprocal of the highest serum
dilution that reduces survival of the pneumococci by at least 50% .
In infants that have received Prevnar 13, opsonophagocytic activity correlates well with seroty pe
specific anti -capsular poly saccharide IgG levels as measured by ELISA. Aserum anti -capsular
polysaccharide antibody concentration of 0.35 µg/mL as measured by ELISA one month after
the third dose as a single antibody reference concentration was used to estimate the
effectiveness of Prevnar 13 against invasive pneumococcal disease ( IPD)in infants and children .
The assay used for this determination is a stand ardized ELISA involving pre- absorption of the
test sera with pneumococcal C -polysaccharide and seroty pe 22F pol ysaccharide to reduce non -
specific background reactivity . The single antibody reference value was based on pooled
efficacy estimates from three p lacebo -controlled IPD efficacy trials with either Prevnar or the
investigational 9 -valent CRM 197conjugate pneumococcal pol ysaccharide vaccine. This
reference concentration is only applicable on a population basis and cannot be used to predict
protection a gainst IPD on an individual basis. Functional antibodies elicited by the vaccine (as
measured b y a dribble opsonophagocy tic activit y [dOPA] antibody assay ) were also evaluated
in infants.
In adults, an antipolysaccharide binding antibody IgG level to predict protection against
invasive pneumococcal disease or non -bacteremic pneumonia has not been defined.
Noninferiorit y trials for Prevnar 13 were designed to show that functional OPA antibody
responses (as measured by a microcolony OPA [mcOPA] antibody assay) for the Prevnar 13
seroty pes are noninferior and for some serot ypes superior to the common serotypes in the
currentl y licensed pneumococcal polysaccharide vaccine (PPSV23). OPA antibody titers
measured in the mcOPA antibody assay cannot be compared dire ctly to titers measured in the
dOPA antibody assay .
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2713NONCLINICAL TOXICOLO GY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Prevnar 13 has not been evaluated for the potential to cause carcinogenicity , genotoxicity , or
impairment of male fertility. In a study in rabbits, no vaccine -related effects were found
regarding reproductive performance including female fertility [see Use in Specific Populations
(8.1)].
14 CLINICAL STUDIES
14.1 Efficacy Data
Prevnar Efficacy Data
Invasive Pneumococcal Di sease (IPD)
Prevnar (Pneumococcal 7- valent Conjugate Vaccine [Diphtheria CRM `197 Protein]) was licensed
in the US for infants and children in 2000, following a randomized, double -blind clinical trial in
a multiethnic population at Northern California Kaise r Permanente (NCKP) from October 1995
through August 20, 1998 , in which 37,816 infants were randomized to receive either Prevnar or
a control vaccine (an investigational meningococcal group C conjugate vaccine [MnCC]) at 2,
4, 6, and 12- 15 months of age. I n this study , the e fficacy of Prevnar against invasive disease due
to S.pneumoniae in cases accrued during this period was 100% in both the per -protocol and
intent -to-treat analy ses (95% confidence interval [ CI]: 75.4% ,100% and 81.7% ,100%,
respectivel y). Data accumulated through an extended follow -up period to April 20, 1999,
resulted in similar efficacy estimates of 97.4% in the per -protocol anal ysis and 93.9% in the
intent -to-treat analy sis(95% CI : 82.7% ,99.9% and 79.6% ,98.5%, respectively ).
Acute O titis Media (AOM)
The efficacy of Prevnar against otitis media was assessed in two clinical trials: a trial in Finnish
infants at the National Public Health Institute and the efficacy trial in US infants at Northern
California Kaiser Permanente (NCKP).
TheFinnish Otitis Media (FinOM) trial was a randomized, double -blind trial in which
1,662 infants were equally randomized to receive either Prevnar or a control vaccin e
Recombivax HB(Hepatitis B vaccine (Recombinant) [Hep B] )at 2, 4, 6, and 12 -15 months of
age. In this study , conducted between December 1995 and March 1999, parents of study
participants were asked to bring their children to the study clinics if the child had respiratory
infections or s ymptoms suggesting acute otitis media (AOM). If AOM was d iagnosed,
tympanocentesis was performed, and the middle -ear fluid was cultured. If S.pneumoniae was
isolated, seroty ping was performed; the primary endpoint was efficacy against AOM episodes
caused b y vaccine serot ypes in the per -protocol population. I n the NCKP trial, the efficacy of
Prevnar against otitis media was assessed from the beginning of the trial in October 1995
through April 1998. The otitis media analy sis included 34,146 infants randomized to receive
either Prevnar (N=17,070), or the control v accine (N=17,076), at 2, 4, 6, and 12 -15 months of
age. In this trial, no routine ty mpanocentesis was performed, and no standard definition of otitis
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28media was used b y stud y physicians. The primary otitis media endpoint was efficacy against all
otitis medi a episodes in the per -protocol population.
The vaccine efficacy against AOM episodes due to vaccine serot ypes assessed in the Finnish
trial, was 57% (95% CI : 44% , 67%) in the per-protocol population and 54% (95% CI:
41%, 64%) in the intent -to-treat populat ion. The vaccine efficacy against AOM episodes due to
vaccine -related serot ypes (6A, 9N, 18B, 19A, 23A), also assessed in the Finnish trial, was 51%
(95% CI :27, 67) in the per -protocol population and 44% (95% CI: 20, 62) in the intent -to-treat
population. There was a nonsignificant increase in AOM episodes caused by seroty pes unrelated
to the vaccine in the per -protocol population, compared to children who received the control
vaccine, suggesting that children who received Prevnar appeared to be at increas ed risk of otitis
media due to pneumococcal serot ypes not represented in the vaccine. However, vaccination
with Prevnar reduced pneumococcal otitis media episodes overall. I n the NCKP trial, in which
the endpoint was all otitis media episodes regardless of etiology , vaccine efficacy was
7%(95% CI: 4%, 10%) and 6% (95% CI: 4% ,9%), respectively , in the per -protocol and
intent -to-treat analy ses.Several other otitis media endpoints were also assessed in the two trials.
Recurrent AOM, defined as 3 episodes in 6 months or 4 episodes in 12 months, was reduced b y
9% in both the per -protocol and intent -to-treat populations (95% CI : 3%,15% in per -protocol
and 95% CI: 4% ,14% in intent -to-treat) in the NCKP trial; a similar trend was observed in the
Finnish trial. The NCKP trial also demonstrated a 20% reduction (95% CI : 2, 35) in the
placement of t ympanostomy tubes in the per -protocol population and a 21% reduction
(95% CI:4, 34) in the intent -to-treat population. Data from the NCKP trial accumulated through
an ex tended follow -up period to April 20, 1999, in which a total of 37,866 children were
included (18,925 in Prevnar group and 18,941 in MnCC control group), resulted in similar otitis
media efficacy estimates for all endpoints.
Prevnar 13 Adult Efficacy Data
The efficacy of Prevnar 13 against vaccine -type (VT) pneumococcal community -acquired
pneumonia (CAP) and IPD was assessed in a randomized, double -blind, placebo -controlled
study conducted over ~ 4 y ears in the Netherlands12(Study 12). A total of 84,496 subjects 65
years and older received a single dose of either Prevnar 13 or placebo in a 1:1 randomization;
42,240 subjects were vaccinated with Prevnar 13 and 42,256 subjects were vaccinated with
placebo.
The primary objective was to demonstrate the efficacy of Prevnar 13 in the prevention of a first
episode of confirmed VT -CAP (defined as presence of ≥2specified clinical criteria; chest X -ray
consistent with CAP as determined b y a central committee of radiologists ; and positive VT-
specific Urinary Antigen D etection assay (UAD) or isolation of VT S. pneumoniae from blood
or other sterile site). The secondary objectives were to demonstrate the efficacy of Prevnar 13 in
the prevention of a first episode of 1) confirmed nonbacteremic/noninvasive (NB/NI) VT- CAP
(an episode of VT-CAP for which the blood culture result and any other sterile site culture
results were negative for S. pneumoniae) and 2) VT-IPD (the presence of S. pneumoniae in a
sterile site).
FDA-CBER-2021-5683-0951364
29Surveillance for suspected pneumonia and IPD began immediat ely after vaccination and
continued through identification of a prespecified number of cases. Subjects who had a CAP or
IPD episode with sy mptom onset less than 14 day s after vaccination were excluded from all
analyses.
The median duration of follow -up per subject was 3.93 years. Prevnar 13 demonstrated
statistically significant vaccine efficacy (VE) in preventing first episodes of VT pneumococcal
CAP ,nonbacteremic/noninvasive (NB/NI) VT pneumococcal CAP ,and VT -IPD (Table 15).
Table 15 -Vaccine Effica cy for the Primary and Secondary Efficacy Endpoints –Per-Protocol Population
Vaccine Group
Prevnar 13 Placebo
N=42240 N=42256
Efficacy EndpointTotal Number
of Episodesn nVE
(%)(95.2% CI)
Prim ary endpoint:
First case of confirmed VT pneumoc occal CAP 139 49 90 45.6 (21.8, 62.5)
Secondary endpoint:
First episode of confirmed NB/NI VT
pneumococcal CAP93 33 60 45 (14.2, 65.3)
Secondary endpoint:
First episode of VT -IPD 35 7 28 75 (41.1, 90.9)
Abbreviations: CAP = community -acquired pneum onia; CI = confidence interval; NB/NI = nonbacteremic/noninvasive; I PD = invasive
pneumococcal disease; VE = vaccine efficacy; VT = vaccine -type.
14.2 Prevnar 13 Clinical Trials in Children 6 Weeks Through 17 Years of Age Infants
and Children 6 Weeks Thr ough 17 Months of Age
Prevnar 13 effectiveness against invasive pneumococcal disease was inferred from comparative
studies to a US- licensed 7-valent pneumococcal conjugate vaccine, Prev nar, in which
Prevnar 13 elicited antipoly saccharide binding and functi onal OPA antibodies, as measured b y
ELISA and dOPA assay s, respectivel y. These studies were designed to evaluate immunologic
noninferiority ofPrevnar 13 to Prevnar.
Clinical trials have been conducted in the US using a 2, 4, 6, and12-15 month schedule.
The US noninferiorit y study2(Study 2) was a randomized, double -blind, active- controlled trial
in which 2 month -old infants were randoml y ass igned to receive either Prevnar 13 or Prevnar in
a 1:1 ratio. The twovaccine groups were well balanced with respect to race, ethnicity , and age
and weight at enrollment. Most subjects were White (69.1%), 19.6% were Black or
African -American, and 2.4% were Asian; 82.1% of subjects were non- Hispanic and non-Latino
and 17.3% were Hispanic or Latino. Overall, 54.0% of subj ects were male infants.
In Stud y 2, immune responses were compared in subjects receiving either Prevnar 13 or Prevnar
using a set of noninferiority criteria. Co-primary endpoints included the percentage of subjects
with serum pneumococcal anti- capsular pol ysaccharide IgG ≥0.35 μg /mL measured one month
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30after the third dose and serum pneumococcal anti -capsular pol ysaccharide IgG geometric mean
concentrations ( GMCs )one month after the fourth dose. The assay used for this determination
wasa standardized ELI SAinvolving pre -absorption of the test sera with pneumococcal
C-polysaccharide and seroty pe 22F pol ysaccharide to reduce non -specific background
reactivit y.Responses to th e 7 common serot ypes in Prevnar 13 and Prevnar recipients were
compared directl y. Res ponses to the 6 additional seroty pes in Prevnar 13 recipients were each
compared to the lowest response observed among the Prevnar serot ypes in Prevnar recipients.
Pneumococcal Immune Responses Following Three Doses
In Stud y 2, the noninferiority criterio n for the proportion of subjects with pneumococcal
anti-capsular pol ysaccharide IgG antibod y concentrations ≥0.35 μg/mL one month after the
third dose was met for 10 of the 13 serotypes. The exceptions were serotypes 6B, 9V, and 3.
Although the response to seroty pes 6B and 9V did not meet the pre -specified noninferiority
criterion, the differences were marginal.
The percentage of infants achieving pneumococcal anti- capsular pol ysaccharide IgG antibod y
concentrations ≥0.35 μg/mL one month after the third dose is shown below (Table 16).
Table 16: Percentage of Subjects With Anti -capsular Antibody Concentration ≥0.35 µg/mL One Month After a Three Dose Series
Administered at 2, 4 and 6 Months of Age ,Study 2a,b,c,d
Serotype Prevnar 13
N=249 -252
(95% CI )Prevna r
N=250 -252
(95% CI )Difference in % responders
(95% CI )
Prevnar Serotypes
4 94.4 (90.9, 96.9) 98.0 (95.4, 99.4) -3.6 (-7.3, -0.1)
6B 87.3 (82.5, 91.1) 92.8 (88.9, 95.7) -5.5 (-10.9, - 0.1)
9V 90.5 (86.2, 93.8) 98.4 (96.0, 99.6) -7.9 (-12.4, - 4.0)
14 97.6 (94.9, 99.1) 97.2 (94.4, 98.9) 0.4 (-2.7, 3.5)
18C 96.8 (93.8, 98.6) 98.4 (96.0, 99.6) -1.6 (-4.7, 1.2)
19F 98.0 (95.4, 99.4) 97.6 (99.4, 99.1) 0.4 (-2.4, 3.4)
23F 90.5 (86.2, 93.8) 94.0 (90.4, 96.6) -3.6 (-8.5, 1.2)
Additional Serotypese
1 95.6 (92.3, 97.8) e 2.8 (-1.3, 7.2)
3 63.5 (57.1, 69.4) e -29.3 (-36.2, - 22.4)
5 89.7 (85.2, 93.1) e -3.1 (-8.3, 1.9)
6A 96.0 (92.8, 98.1) e 3.2 (-0.8, 7.6)
7F 98.4 (96.0, 99.6) e 5.6 (1.9, 9.7)
19A 98.4 (96.0, 99.6) e 5.6 (1.9, 9.7)
aStudies conducted in US NCT00373958 (Study 2).
bEvaluable I mmunogenicity Population.
cNoninferiority was met when the lower limit of the 95% CI for the difference between groups (Prevnar 13 minus Prevnar) was greater
than -10%.
dAntibody measured by a standardized ELISA in volving pre -absorption of the test sera with pneumococcal C -polysaccharide and serotype
22F polysaccharide to reduce non -specific background reactivity.
eComparison for the 6 additional serotypes was to the lowest responder of the 7 common serotypes in Pr evnar recipients, which for this
analysis was serotype 6B (92.8%; 95% CI : 88.9, 95.7).
FDA-CBER-2021-5683-0951366
31Functional dOPA antibody responses were elicited for all 13 serot ypes, as shown in Table 17.
Table 17: Pneumococcal dOPA Antibody Geometric Mean Titers One Month After a Three Dose Series Administered at 2, 4 and 6
Months of Age ,Study 2a,b,c
Serotype Prevnar 13
N=91 -94
(95% CI )Prevnar
N=89 -94
(95% CI )
Prevnar Serotypes
4 359 (276, 468) 536 (421, 681)
6B 1055 (817, 1361) 1514 (1207, 1899)
9V 4035 (2933, 5553) 3259 (2288, 4641)
14 1240 (935, 1646) 1481 (1133, 1934)
18C 276 (210, 361) 376 (292, 484)
19F 54 (40, 74) 45 (34, 60)
23F 791 (605, 1034) 924 (709, 1204)
Additional Serotypes
1 52 (39, 69) 4(4, 5)
3 121 (92, 158) 7(5, 9)
5 91 (67, 123) 4(4, 4)
6A 980 (783, 1226) 100 (66, 152)
7F 9494 (7339, 12281) 128 (80, 206)
19A 152 (105, 220) 7(5, 9)
aStudies conducted in US NCT00373958 (Study 2).
bThe dOPA (opsonophagocytic activity) antibody assay measures the ability of immune sera, in conjunction with complement, to
mediate the uptake and killing of S. pneumoniae by phagocytic cells.
cEvaluable I mmunogenicity Population .
Pneumococcal Immune Responses Following Four Doses
In Stud y 2, post -dose 4 antibody concentrations were higher for all 13 seroty pes than those
achieved after the third dose. The noninferiority criterion for pneumococcal anti -capsular
polysaccharide GMCs after 4 doses was met for 12 of the 13 pneumococcal seroty pes. The
noninferiority criterion was not met for the response to serot ype 3 (Table 18).
Table 18: Pneumococcal IgG GMCs (µg/mL) One Month After a Four Dose Series Administered at 2, 4, 6 and 12 -15 Months ,Study 2a,b,c,d
Serotype Prevnar 13
N=232 -236
(95% CI )Prevnar
N=222 -223
(95% CI )GMC Ratio
(95% CI )
Prevnar Serotypes
4 3.73(3.28, 4.24) 5.49 (4.91, 6.13) 0.68 (0.57, 0.80)
6B 11.53 (9.99, 13.30) 15.63 (13.80, 17.69) 0.74 (0.61, 0.89)
9V 2.62 (2.34, 2.94) 3.63 (3.25, 4.05) 0.72 (0.62, 0.85)
14 9.11 (7.95, 10.45) 12.72 (11.22, 14.41) 0.72 (0.60, 0.86)
18C 3.20 (2.82, 3 .64) 4.70 (4.18, 5.28) 0.68 (0.57, 0.81)
19F 6.60 (5.85, 7.44) 5.60 (4.87, 6.43) 1.18 (0.98, 1.41)
23F 5.07 (4.41, 5.83) 7.84 (6.91, 8.90) 0.65 (0.54, 0.78)
Additional Serotypese
1 5.06 (4.43, 5.80) e 1.40 (1.17, 1.66)
3 0.94 (0.83, 1.05) e 0.26 (0.22, 0.30)
5 3.72 (3.31, 4.18) e 1.03 (0.87, 1.20)
6A 8.20 (7.30, 9.20) e 2.26 (1.93, 2.65)
7F 5.67 (5.01, 6.42) e 1.56 (1.32, 1.85)
19A 8.55 (7.64, 9.56) e 2.36 (2.01, 2.76)
a Studies conducted in US NCT00373958 (Study 2).
bEvaluable I mmunogenicity Population.
cNoninferiority was declared if the lower limit of the 2 -sided 95% CI for Geometric Mean Ratio (Prevnar 13:Prevnar) was greater than
0.5.
dAntibody measured by a standardized ELISA involving pre -absorption of the test sera with pneumococcal C -polysaccharide and
serotype 22F polysaccharide to reduce non -specific background reactivity.
eComparison for the 6 additional serotypes was to the lowest responder of the 7 common serotypes in Prevnar recipients, which for this
analysis was serotype 9V ( 3.63; 95% CI 3.25, 4.05).
FDA-CBER-2021-5683-0951367
32Following the fourth dose, the functional dOPA antibody response for each seroty pe was
quantitatively greater than the response following the third dose (see Table 19).
Table 19: Pneumococcal dOPA Antibody Geometric Mean Titers O ne Month After the Fourth Dose -Evaluable Toddler Immunogenicity
Population, Study 2a,b
Serotype Prevnar 13
N=88 -92
(95% CI )Prevnar
N=92 -96
(95% CI )
Prevnar Serotypes
4 1180 (847, 1643) 1492 (1114, 1999)
6B 3100 (2337, 4111) 4066 (3243, 5098)
9V 11856 (8810, 15955) 18032 (14125, 23021)
14 2002 (1453, 2760) 2366 (1871, 2992)
18C 993 (754, 1308) 1722 (1327, 2236)
19F 200 (144, 276) 167 (121, 230)
23F 2723 (1961, 3782) 4982 (3886, 6387)
Additional Serotypes
1 164 (114, 237) 5(4, 6)
3 380 (300, 482 ) 12 (9, 16)
5 300 (229, 393) 5(4, 6)
6A 2242 (1707, 2945) 539 (375, 774)
7F 11629 (9054, 14938) 268 ( 164, 436)
19A 1024 (774, 1355) 29 (19, 44)
aStudies conducted in US NCT00373958 (Study 2).
bThe dOPA (opsonophagocytic activity) antibody assay me asures the ability of immune sera, in conjunction with complement, to
mediate the uptake and killing of S. pneumoniae by phagocytic cells.
Previously Unvaccinated Older Infants and Children 7 Months Through 5 Years of Age
In an open -label descriptive s tudy of Prevnar 13 in Poland4(Study 4),children 7 months through
11 months of age , 12months through 23 months of age and 24 months through 5 y ears of age
(prior t o the 6thbirthday )who were na ïve to pneumococcal conjugate vaccine, were giv en 3, 2 or
1 dos e of Prevnar 13 respectivel y, according to the age -appropriate schedules in Table 2 .
Serum IgG concentrations were measured one month after the final dose in each age group and
the data are shown in Table 20.
Table 20: Pneumococcal Anti -capsular Polysaccha ride IgG Antibody Geometric Mean Concentrations (μg/mL) One Month After the Final
Prevna r13 Catch -Up Dose in Pneumo coccal Vaccine Naïve Children 7 Months Through 5 Years of Age by Age Group, Study 4a,b
Serotype 3 doses Prevnar 13
7through 11months
N=83-84
(95% CI )2 doses Prevnar 13
12through 23months
N=104 -110
(95% CI )1 dose Prevnar 13
24months through 5years
N=135 -152
(95% CI )
1 2.88 (2.44, 3.39) 2.74 (2.37, 3.16) 1.78 (1.52, 2.08)
3 1.94 (1.68, 2.24) 1.86 (1.60, 2.15) 1.42 (1.23, 1.64)
4 3.63 (3.11, 4.23) 4.28 (3.78, 4.86) 3.37 (2.95, 3.85)
5 2.85 (2.34, 3.46) 2.16 (1.89, 2.47) 2.33 (2.05, 2.64)
6A 3.72 (3.12, 4.45) 2.62 (2.25, 3.06) 2.96 (2.52, 3.47)
6B 4.77 (3.90, 5.84) 3.38 (2.81, 4.06) 3.41 (2.80, 4.16)
7F 5.30 (4.54, 6.18) 5.99 (5.40, 6.65) 4.92 (4.26, 5.68)
9V 2.56 (2.21, 2.96) 3.08 (2.69, 3.53) 2.67 (2.32, 3.07)
14 8.04 (6.95, 9.30) 6.45 (5.48, 7.59) 2.24 (1.71, 2.93)
18C 2.77 (2.39, 3.23) 3.71 (3.29, 4.19) 2.56 (2.17, 3.03)
19A 4.77 (4.28, 5.33) 4.94 (4.31, 5.65) 6.03 (5.22, 6 .97)
19F 2.88 (2.35, 3.54) 3.07 (2.68, 3.51) 2.53 (2.14, 2.99)
23F 2.16 (1.82, 2.55) 1.98 (1.64, 2.39) 1.55 (1.31, 1.85)
a Studies conducted in Poland NCT00452452 (Study 4).
bOpen label administration of Prevnar 13.
Note –Clinical Trials.gov NCT number isas follows: NCT00452452 (Poland).
FDA-CBER-2021-5683-0951368
33Children 15 Months Through 59 Months of Age Previously Vaccinated with Prevnar
In an open -label descriptive study in the US5(Study 5), children 15 months through 59 months
previously vaccinated with 3 or 4 doses of Pr evnar, received 2 doses of Prevnar 13 (children >15
through 23 months of age) or 1 dose of Prevnar 13 (children 24 months through 59 months of
age). The data following one dose of Prevnar 13 in children 24 months through 59 months of age
are shown in Table 21.
Table 21: Pneumococcal Anti -capsular Polysaccharide IgG Antibody Geometric Mean Concentrations (μg/mL) One Month After One
Prevnar 13 Catch -Up Dose in Children 24 Through 59 Months of Age With 3 or 4 Prior Doses of Prevnar, US Catch -Up Study 5a,b
Serotype 1 dose Prevnar 13
24 months through 59 months
N=173 -175
(95% CI )
1 2.43 (2.15, 2.75)
3 1.38 (1.17, 1.61)
5 2.13 (1.89, 2.41)
6A 12.96 (11.04, 15.21)
7F 4.22 (3.74, 4.77)
19A 14.18 (12.37, 16.25)
a Studies conducted in US NCT00761631 (Study 5 ).
bOpen label administration of Prevnar 13.
Children 5 T hrough 17 Years of Age
In a US study5(Study 5), a single dose of Prevnar 13 was administered to children 5 through
9years of age , who were previously vaccinated with at least onedose of Prevnar, and to
pneumococcal vaccine -naïve children 10 through 17 y ears of age .
In children 5 through 9 years of age, serotype -specific IgG concentrations measured 1 month
after vaccination were noninferior (i.e., the lower limit of the 2 -sided 95% CI for the geometric
mean ratio [GMR ]of >0.5) to the corresponding IgG concentrations in toddlers (Study 3) 1
month after a fourth pneumococcal vaccination (after the 4thdose of Prevnar for the 7 common
seroty pes and after the 4thdose of Prevnar 13 for the 6 additio nal serotypes) as shown in Tables
22and 23respectivel y.
FDA-CBER-2021-5683-0951369
34Table 22: Pneumococcal IgG GMCs (µg/mL) One Month After Vaccination for 7 Common Serotypes, Prevnar 13 in Children 5 through 9
Years of Age in Study 5 Relative to Prevnar in Study 3 (Post -toddler)a,g,h
Vaccine Group (as Enrolled/Randomized)
Prevnar 13
5 Through 9 Years
(Study 5)Prevnar
Post-Toddler Dose
(Study 3)
Serotype nbGMCc(95% CId) nbGMCc(95% CId)GMC
Ratioe(95% CIf)
Common
4 169 8.45 (7.24, 9.87) 173 2.79 (2.45 , 3.18) 3.03 (2.48, 3.71)
6B 171 53.56 (45.48, 63.07) 173 9.47 (8.26, 10.86) 5.66 (4.57, 6.99)
9V 171 9.51 (8.38, 10.78) 172 1.97 (1.77, 2.19) 4.83 (4.10, 5.70)
14 169 29.36 (24.78, 34.78) 173 8.19 (7.31, 9.18) 3.58 (2.93, 4.39)
18C 171 8.23 (7.13, 9.51) 173 2.33 (2.05, 2.65) 3.53 (2.91, 4.29)
19F 171 17.58 (14.95, 20.67) 173 3.31 (2.87, 3.81) 5.31 (4.29, 6.58)
23F 169 11.26 (9.79, 12.95) 173 4.49 (3.86, 5.23) 2.51 (2.04, 3.08)
aStudies conducted in US NCT00761631 (Stud y 5) and NCT00444457 (Study 3).
bn = Number of subjects with a determinate antibody concentration for the specified serotype.
cGeometric mean concentrations (GMCs) were calculated using all subjects with available data for the specified blood draw. GMC a fter a 4 -dose
vaccination series with Prevnar (Study 3, post -toddler).
dConfidence intervals (CI s) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the
concentrations.
eRatio of GMCs: Prevnar 13 (Study 5) to Prevnar (Study 3) reference.
fCIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean differen ce of the logarithms of
the measures [Prevnar 13 (Study 5) –Prevnar (Study 3)].
gEvaluable I mmunogenicity Population.
hNoninferiority was declared if the lower limit of the 2 -sided 95% CI for geometric mean r atio was greater than 0. 5.
Table 23: Pneumococcal IgG GMCs (µg/mL) One Month After Vaccination for Additional 6 Serotypes, Pr evnar 13 in Children 5 through 9
Years of Age in Study 5 Relative to Prevnar 13 in Study 3 (Post -toddler)a,g.h
Vaccine Group (as Enrolled/Randomized)
Prevnar 13
5 Through 9 Years
(Study 5)Prevnar 13
Post-Toddler Dose
(Study 3)
Serotype nbGMCc(95% CId) nbGMCc(95% CId)GMC
Ratioe(95% CIf)
Additional
1 171 3.57 (3.05, 4.18) 1068 2.90 (2.75, 3.05) 1.23 (1.07, 1.42)
3 171 2.38 (2.07, 2.74) 1065 0.75 (0.72, 0.79) 3.17 (2.78, 3.62)
5 171 5.52 (4.82, 6.32) 1068 2.85 (2.72, 2.98) 1.94 (1.71, 2.20)
6A 169 21.51 (18.15, 25.51) 1063 7.11 (6.78, 7.46) 3.03 (2.64, 3.47)
7F 170 6.24 (5.49, 7.08) 1067 4.39 (4.18, 4.61) 1.42 (1.24, 1.62)
19A 170 17.18 (15.01, 19.67) 1056 8.44 (8.05, 8.86) 2.03 (1.78, 2.32)
aStudies conducted in US NCT00761631 (Study 5) and NCT00444457 (Study 3).
bn = Number of subjects with a determinate antibody concentration for the specified serotype.
cGeometric mean concentrations (GMCs) were calculated using all subjects with available data for the specified blood draw. GMC after a 4 -dose
vaccination series with Prevnar 13 (Study 3, post -toddler).
dConfidence intervals (CI s) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the
concentrations.
eRatio of GMCs: Prevnar 13 (Study 5) to Prevnar 13 (Study 3).
fCIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean differen ce of the logarithms of
the measures [Prevnar 13 (Study 5) –Prevnar 13 (Study 3)].
gEvaluable I mmunogenicity Population .
hNoninferiority was declared if the lower l imit of the 2 -sided 95% CI for geometric mean r atio was greater than 0. 5.
In children 10 through 17 y ears of age OPA GMTs , as measure d by the mcOPA assay , 1month
after vaccination were noninferior ( i.e.,the lower limit of the 2 -sided 95% CI for the GMR of
FDA-CBER-2021-5683-0951370
35>0.5) to mc OPA GMTs in the 5 through 9 year old group for 12 of 13 seroty pes (excep t for
seroty pe3), as shown in Table 24.
Table 24: Comparison of Pneumococcal mcOPA GMTs One Month After Vaccina tion, Prevnar 13, in Children 10 through 17 Years of Age
Relative to Prevnar 13 in Children 5 through 9 Years of Agea,g,h,i
Vaccine Group (as Enrolled)
Prevnar 13
(10 through 17 Years)Prevnar 13
(5 through 9 Years)
Serotype nbGMTc(95% CId) nbGMTc(95% CId)GMT
Ratioe(95% CIf)
Common
4 188 6912 (6101, 7831) 181 4629 (4017, 5334) 1.5 (1.24, 1.80)
6B 183 14224 (12316, 16427) 178 14996 (13164, 17083 ) 0.9 (0.78, 1.15)
9V 186 4485 (4001, 502 8) 180 4733 (4203, 5328) 0.9 (0.80, 1.12)
14 187 6894 (6028, 7884) 176 4759 (4120, 5497) 1.4 (1.19, 1.76)
18C 182 6263 (5436, 7215) 175 8815 (7738, 10041) 0.7 (0.59, 0.86)
19F 184 2280 (1949, 266 8) 178 1591 (1336, 1893) 1.4 (1.14, 1.81)
23F 187 3808 (3355, 432 3) 176 3245 (2819, 373 6) 1.2 (0.97, 1.42)
Additional
1 189 322 (275, 378) 179 191 (165, 221) 1.7 (1.36, 2.10)
3 181 114 (101, 130) 178 203 (182, 226) 0.6 (0.48, 0.67)
5 183 360 (298, 43 6) 178 498 (437, 568) 0.7 (0.57, 0.91)
6A 182 9928 (8457, 1165 5) 178 7514 (6351, 889 1) 1.3 (1.05, 1.67)
7F 185 6584 (5829, 743 6) 178 10334 (9099, 1173 7) 0.6 (0.53, 0.76)
19A 187 1276 (1132, 1439) 180 1180 (1048, 13 29) 1.1 (0.91, 1.28)
aStudies conducted in US NCT00761631 (Study 5).
bn= Number of subjects with a determinate antibody titer for the specified serotype.
cGeometric mean titers (GMTs) were calculated using all subjects with available data for the specified blood draw.
dConfidence intervals (CI s) are back transformations of a confidence interval based on the Student t distribution for the mean logarithm of the
titers.
eRatio of GMTs: Prevnar 13(10 through 17 years of age) to Prevnar 13 (5 through 9 years of age) .
fCIs for the ratio are back transformations of a confidence interval based on the Student t distribution for the mean differen ce of the logarithms of
the measures [Prevnar 13(10 thro ugh 17 years of age) –Prevnar 13(5 through 9 years of age)] Study 5.
gEvaluable I mmunogenicity Population.
h Noninferiority was declared if the lower l imit of the 2 -sided 95% CI for geometric mean r atio was greater than 0. 5.
iIndividual mcOPA antibody a ssay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of
calculating the mcOPA antibody GMT.
14.3 Prevnar 13 Immunogenicity Clinical Trials in Adults
SixPhase 3 or Phase 4 clinical trials6-8,10,11,13were co nducted in the US and Europe evaluating
the immunogenicit y of Prevnar 13 in different adult age groups, in individuals who were either
not previously vaccinated with PPSV23 (PPSV23 unvaccinated ) or who had received one dose
of PPSV23 (PPSV23 previously vaccinated).
Each stud y included healthy adults and immunocompetent adults with stable underl ying
conditions including chronic cardiovascular disease, chronic pulmonary disease, renal disorders,
diabetes mellitus, chronic liver disease, and medical risk condi tions and behaviors
(e.g., alcoholism and smoking) that are known to increase the risk of serious pneumococcal
pneumonia and invasive pneumococcal disease. A stable medical condition was defined as a
medical condition not requiring significant change in th erapy (i.e., change to new therap y
category due to worsening disease) or hospitalization for worsening disease 6-12 weeks prior to
receipt of the study vaccine.
FDA-CBER-2021-5683-0951371
36Immune responses elicited by Prevnar 13 and PPSV23 were measured by a mcOPA antibody
assay forthe 13 pneumococcal seroty pes contained in Prevnar 13. Serot ype-specific mcOPA
antibody GMTs measured 1 month after each vaccination were calculated. For the 12 serot ypes
in common to both vaccines, noninferiorit y between vaccines was met if the lower limit of the
2-sided 95% confidence interval (CI) of the GMT ratio (Prevnar 13/PPSV23) was greater than
0.5.
The response to the additional seroty pe 6A, which is contained in Prevnar 13 but not in PPSV23,
was assessed b y demonstration of a ≥4-fold increase in the anti -6A mcOPA antibody titer above
preimmunization levels. A statistically significantly greater response for Prevnar 13 was defined,
for the difference in percentages (Prevna r 13 minus PPSV23) of adults achieving a ≥4-fold
increase in anti -6A mcOPA antibody titer, as the lower limit of the 2 -sided 95% CI greater than
zero. For comparison of mcOPA antibody GMTs, a statistically greater response for seroty pe 6A
was defined as th e lower limit of the 2 -sided 95% CI of the GMT ratio (Prevnar 13/PPSV23)
greater than 2.
Of the 6Phase 3 or Phase 4clinical trials, 2 noninferiorit y trials6,7were conducted in which the
immune responses to Prevnar 13 were compared with the immune respo nses to PPSV23; one in
PPSV23 unvaccinated adults aged 18 through 64 years6(Study 6), and one in PPSV23
previously vaccinated adults aged ≥70 y ears7(Study 7). A third study compared immune
responses to a single dose of Prevnar 13 to the response to Prevnar 13 administered one y ear
after a dose of PPSV23 in adults aged 60 through 64 years who were PPSV23 unvaccinated at
enrollmen t8 (Study 8). The study also compared immune responses of PPSV23 as a single dose
to the responses to PPSV23 administered one year after a dose of Prevnar 13.Two studies
assessed the concomitant administration of Prevnar 13 with seasonal inactivated Fluar ix (IIV3)
in the US10(Study 10) and E urope11(Study 11).One study (Study 13)assessed the concomitant
administration of Prevnar 13 with seasonal inactivated Fluzone Quadrivalent (IIV4) in PPSV23
previously vaccinated adults ≥50 y ears of age in the US.
Overall across the clinical studies evalua ting the immunogenicit y of Prev nar 13 in adults ,
persons 18through 64 y ears o f age responded at least as well as persons 65 years and older , the
age group evaluated in a clinic al endpoint efficacy trial .
Clinical Trials Conducted in PPSV23 Unvaccinated A dults
In an active -controlled modifiedadouble -blind clinical trial6(Study 6)of Prevna r 13 in the US,
PPSV23 unvaccinated adults aged 60 through 64 years were randoml y assigned (1:1) to receive
Prevnar 13 or PPSV23. In addition, adults aged 18 through 49 years and 50 through 59 years
were enrolled and received one dose of Prevnar 13 (open- label).
aModified double- blind means that the site staff dispensing and administering the vaccine were unblinded, but all
other study personnel including the principal investigator and subject w ere blinded.
FDA-CBER-2021-5683-0951372
37In adults aged 60 through 64 years, the mc OPA antibody GMTs elicited b y Prevnar 13were
noninferior to those elicited by PPSV23 for the 12 seroty pes in common to both vaccines (see
Table 24 ). In addition, the lower limit of the 95% confidence interval for the mcOPA antibody
GMT ratio ( Prevnar 13/PPSV23) was greater than 1 for 8 of the s erotypes in common .
For seroty pe 6A, which is unique to Prevnar 13, the proportion of subjects with a ≥4- fold
increase after Prevnar 13 (88.5%) was statistically significantl y greater than after PPSV23
(49.3 %) in PPSV23 -unvaccinated adults aged 60 through 64 y ears. OPA antibody GMTs for
seroty pe 6A were statistically significantly greater after Prevnar 13 compared with after PPSV23
(see Table 25).
The mcOPA antibody GMTs elicited by Prevnar 13 in adults aged 50 through 59 years were
noninferior to the corresponding mcOPA antibody GMTs elicited by Prevnar 13 in adults aged
60through 64 years for all 13 seroty pes(seeTable 25).
In adults aged 18 through 49 y ears, the mcOPA antibody GMTs elicited b y Prevnar 13 were
noninferior to those elicited by Prevnar 13 in adults aged 60 through 64 y ears for all 13 serot ypes
(see Table 25).
FDA-CBER-2021-5683-0951373
38Table 25: mcOPA Antibody GMT s in PPSV23 -Unvaccinated Adults Aged 18 Through 49 Years or Aged 50 Through 59 Years Given
Prevnar 13 and in Adults Aged 60 Through 64 Years Given Prevnar 13 or PPSV23 (Study 6)a,b,c,d,e
Prevnar 13 Prevnar 13 Prevnar 13 PPSV23Prevnar 13
18-49 Relative
to 60 -64 YearsPrevnar 13
50-59 Relative to
60-64 YearsPrevnar 13
Relative
to PPSV23,
60-64 Yearsg18-49 Yearsf
N=836 -86650-59 Yearsf
N=350 -38460-64 Years
N=359 -40460-64 Years
N=367 -402
SerotypeGMT GMT GMT GMTGMT Ratio
(95% CI )GMT Ratio
(95% CI )GMT Ratio
(95% CI )
1353211 158 1192.4
(2.03, 2.87)1.3
(1.07, 1.65)1.3
(1.07, 1.65)
39194 96 901.0
(0.84, 1.13)1.0
(0.82, 1.18)1.1
(0.89, 1.29)
447472904 2164 14052.3
(1.92, 2.76)1.3
(1.06, 1.70)1.5
(1.18, 2.00)
5386322 236 1981.9
(1.55, 2.42)1.4
(1.08, 1.74)1.2
(0.95, 1.50)
6Ah 57464469 2766 3432.2
(1.84, 2.67)1.6
(1.28, 2.03)8.1
(6.11, 10.67)
6B98133350 2212 9984.9
(4.13, 5.93)1.5
(1.20, 1.91)2.2
(1.70, 2.89)
7F32491807 1535 8292.9
(2.41, 3.4 9)1.2
(0.98, 1.41)1.9
(1.52, 2.26)
9V33392190 1701 10122.9
(2.34, 3.52)1.3
(1.08, 1.53)1.7
(1.40, 2.02)
1429831078 733 8194.9
(4.01, 5.93)1.5
(1.14, 1.89)0.9
(0.69, 1.16)
18C39892077 1834 10742.3
(1.91, 2.79)1.1
(0.89, 1.44)1.7
(1.32, 2 .21)
19A1580968 691 3682.3
(2.02, 2.66)1.4
(1.17, 1.68)1.9
(1.53, 2.30)
19F1533697 622 6363.0
(2.44, 3.60)1.1
(0.89, 1.41)1.0
(0.78, 1.23)
23F1570531 404 874.2
(3.31, 5.31)1.3
(0.96, 1.80)4.6
(3.37, 6.38)
GMT, Geometric Mean Titer.
a Study conducted in US NCT00427895 (Study 6).
b Noninferiority was defined for the 13 serotypes in adults aged 18 to 49 years, for the 12 common serotypes in adults aged 60 to 64 years and
for the 13 serotypes in adults aged 50 to 59 years as the lower limit o f the 2 -sided 95% CI for GMT ratio greater than 0.5.
cmcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured.
dIndividual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of
calculating the mcOPA antibody GMT.
eEvaluable I mmunogenicity Population.
fOpen label administration of Prevnar 13 .
gFor serotype 6A, which is unique to Prevnar 13, a statistically significantly greater response was d efined for analysis in cohort 1 as the
lower limit of the 2 -sided 95% CI for the GMT ratio (Prevnar 13/PPSV23) greater than 2 .
h6A is a serotype unique to Prevnar 13 but not contained in PPSV23.
Clinical Trials Conducted in PPSV23 Previously V accinated Adults
In a Phase 3active -controlled, modified double -blind clinical trial7(Study 7) of Prevnar 13 in the
US and Sweden ,PPSV23 previously vaccinated adults aged ≥70 years who had received
onedose of PPSV23 ≥5years prior were randomly assigned (1:1) to receive either Prevnar 1 3 or
PPSV23.
FDA-CBER-2021-5683-0951374
39The mcOPA antibody GMTs elicited by Prevnar 13 were noninferior to those elicited by
PPSV23 for the 12 serotypes in common, when Prevnar 13 or PPSV23 were administered at a
minimum of 5 y ears after a prior dose of PPSV 23. In addition, the lower limit of the 95%
confidence interval for the mcOPA antibody GMT ratio (Prevnar 13/PPSV23) was greater than 1
for 9 of the serot ypes in common.
For seroty pe 6A, which is unique to Prevnar 13, the proportion of subjects with a ≥4- fold
increase in mcOPA antibody titers after Prevnar 13 (71.1%) was statistically significantl ygreater
than after PPSV23 (27.3%) in PPSV23 previously vaccinated adults aged ≥70years. mcOPA
antibody GMTs for seroty pe 6A were statistically significantl ygreater after Prevnar 13
compared with after PPSV23.
This clinical trial demonstrated that in adults aged ≥70 y ears and previousl y vaccinated with
PPSV23 ≥5 years prior, vaccination with Prevnar 13 elicited noninferior immune responses as
compared with re-vaccination with PPSV23 (see Table 26).
Table 26: mcOPA Antibody GMTs in PPSV23 -Previously V accinated Adults Aged ≥70 Years Given Prevnar 13 or PPSV23
(Study 7)a,b,c,d,e,f
SerotypePrevnar 13
N=400 -426PPSV23
N=395 -445Prevnar 13
Relative to PPSV23
GMT GMT GMT Ratio (95% CI )
1 93 66 1.4 (1.14, 1.72)
3 59 53 1.1 (0.92, 1.31)
4 613 263 2.3 (1.76, 3.10)
5 100 61 1.6 (1.35, 2.00)
6Ag1056 160 6.6 (5.14, 8.49)
6B 1450 565 2.6 (2.00, 3.29)
7F 559 481 1.2 (0.97, 1.39)
9V 622 491 1.3 (1.08, 1.49)
14 355 366 1.0 (0.76, 1.23)
18C 972 573 1.7 (1.33, 2.16)
19A 366 216 1.7 (1.40, 2.07)
19F 422 295 1.4 (1.16, 1.77)
23F 177 53 3.3 (2.49, 4.47)
GMT ,Geometric Mean Titer .
a Study conducted in US and Sweden NCT00546572 (Study 7).
bFor the 12 common serotyp es, noninferiority was defined as the lower limit of the 2- sided 95% CI for GM Tratio (Prevnar 13/PPSV23) greater
than 0.5.
cFor serotype 6A, which is unique to Prevnar 13, a statistically significantly greater response was defined as the lower limit of the 2 -sided 95%
CI for the GM Tratio (Prevnar 13/PPSV23) greater than 2.
dmcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured.
eIndividual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of
calculating the mcOPA antibody GMT.
fEvaluable I mmunogenicity Population.
g 6A is a serotype unique to Prevnar 13 but not contained in PPSV23.
Clinical Trial of Se quential V accination of Prevnar 13and PPSV 23 in PPSV23
Unvaccinated Adults
In a randomized clinical trial conducted in PPSV23 -unvaccinated adults 60 through 64 years of
age8(Study 8), 223 subjects received PPSV23 followed by Prevnar 13 one y ear later
(PPSV23/Prevnar 13), and 478 received only Prevnar 13. mcOPA antibody titers were measured
1 month after vaccination with Prevnar 13 and are shown in Table 26. mcOPA antibody GMTs
in those that received Prevnar 13 one year after PPSV23 were diminished when compared to
those who received Prevn ar 13 alone. Similarly , in exploratory anal yses in PPSV23 previously
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40vaccinated adults ≥ 70 years of age in Study 7, diminished mcOPA antibody GMTs were
observed in those that received Prevnar 13 one year after PPSV23 when compared to those who
received Prevnar 13 alone.
Table 27: mcOPA Antibody GMTs for the Prevnar 13 Serotypes in PP SV23 Unvaccinated Adults Aged 60 Through 64 Years Given
Prevnar 13 Alone or Prevnar 13 One Year After PPSV23 (Study 8) (PPSV23/Prevnar 13)a,b,c,d
Prevnar 13
N=410 -457PPSV23/Prevnar 13
N=180 -196
Serotype GMT (95% CI) GMT (95% CI)
1 219 (191, 252) 88 (72, 109)
3 78 (69, 88) 54 (45, 65)
4 2590 (2257 , 2973 ) 988 (802, 1218 )
5 258 (218, 305) 112 (90, 139)
6Ae2947 (2536 , 3426 ) 1210 (962, 1522 )
6B 2165 (1845 , 2540 ) 832 (654, 1059 )
7F 1518 (1339 , 1721 ) 407 (342, 485)
9V 1279 (1142 , 1432 ) 495 (426, 575)
14 790 (663, 941) 515 (402, 659)
18C 1683 (1437 , 1971 ) 650 (504, 839)
19A 717 (629, 818) 299 (248, 361)
19F 812 (702, 939) 360 (293, 442)
23F 384 (312, 472) 142 (104, 193)
GMT =Geometric Mean Titer.
a Study conducted in US NCT00574548 (Study 8).
bEvaluable I mmunogenicity Population.
cmcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured.
dIndividual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLO Qfor the purpose of
calculating the mcOPA antibody GMT.
e6A is a serotype unique to Prevnar 13 but not contained in PPSV23.
Also in Study 8, 266 subjects received Prevnar 13 followed by PPSV23 one y ear later
(Prevnar 13/PPSV23). mc OPA antibody GMTs fol lowing PPSV23 admi nistered one year after
Prevnar 13 (Prevnar 13 /PPSV23) were noninferior to those following a single dose of
PPSV23 (N=237) for the 12 common serotypes [the lower limit of the 95% CI for the GMT ratio
[Prevnar 13/PPSV23 relative to PPSV23] was >0.5 ] (see Table 27). In Study 6, which was
conducted in PPSV23- unvaccinated adults 60 through 64 years of age, 108 subjects received
PPSV23 3.5 to 4 y ears after Prevnar 13 (Prevnar 13/PPSV23) and 414 received a single dose of
PPSV23. Higher serot ype-specific mcOPA antibody GMT ratios [(Prevnar 13/PPSV23) /
PPSV23] were generall y observed compared to the one year dosing interval in Study 8.
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41Table 28: mcOPA Antibody GMTs for the Prevnar 13 Serotypes in PPSV23 -Unvaccinated Adults Aged 60 Through 64 Yea rs Given
PPSV23 One Year After Prevnar 13 Relative to PPSV23 Alone (Study 8)a,b,c,d
Prevnar 13/PPSV23
N=216 -233PPSV23
N=214 -229GMT Ratio (Prevnar 13/PPSV23 ) /
PPSV23
Serotype GMT 95% CI GMT 95% CI Ratio 95% CI
1 155 (131 , 182) 161 (131, 198) 1.0 (0.74, 1.25)
3 127 (111 , 145) 83 (71, 98) 1.5 (1.23, 1.87)
4 1409 (1202 , 1651 ) 1468 (1139 , 1893 ) 1.0 (0.71, 1.29)
5 220 (184 , 264) 178 (144, 222) 1.2 (0.93, 1.64)
6Ae1366 (1122 , 1663 ) 400 (306, 524) 3.4 (2.45, 4.77)
6B 1345 (1113 , 1625 ) 875 (689, 1111) 1.5 (1.14, 2.08)
7F 748 (653 , 857) 719 (598, 865) 1.0 (0.83, 1.31)
9V 848 (731 , 984) 824 (694, 977) 1.0 (0.82, 1.29)
14 711 (580 , 872) 869 (677, 1115 ) 0.8 (0.59, 1.13)
18C 1115 (925, 1344 ) 912 (707, 1177 ) 1.2 (0.89, 1.67)
19A 471 (408 , 543) 390 (318, 477) 1.2 (0.94, 1.55)
19F 819 (697 , 963) 626 (504, 779) 1.3 (1.00, 1.71)
23F 216 (169 , 277) 84 (62, 114) 2.6 (1.74, 3.79)
GMT =Geometric Mean Titer.
aStudy conducted in US NCT00574548 (Study 8).
bEvaluable I mmunogenicity Population.
cmcOPA antibody for the 11 serotypes unique to PPSV23 but not contained in Prevnar 13 were not measured.
dIndividual mcOPA antibody assay values below the assay LLOQ (lower limit of quantitation) were set at 0.50*LLOQ for the purpose of
calculating the mcOPA antibody GMT.
e6A is a serotype unique to Prevnar 13 but not contained in PPSV23. Anti-6A mcOPA antibody GMTs were descriptive in nature.
14.4 Concomitant Vaccine Administration
Infants and Toddlers
The con comitant administration of routine US infant vaccines [see Drug Interactions (7.1) ]with
Prevnar 13 was evaluated in two studies: S tudy 2[see Clinical Studies (14.2)] , Pneumococcal
Immune Responses Following Three Doses2,and the US lot consistency study3(Study 3). In
Study 3,subjects were randomly assigned to receive one of 3 lots of Prevnar 13 or Prevnar in a
2:2:2:1 ratio. The total number of infants vaccinated was 6632(Study 2) and 16993(Study 3).
Immune responses to concomitant vaccine antigens were compared in infants receiving Prevnar
and Prevnar 13. R esponses to diphtheria toxoid, tetanus toxoid, pertussis, polio ty pes 1, 2, and 3,
hepatitis B, PRP -T, PRP -OMP, measles, and varicella antigens in Prevnar 13 recipients were
similar to those in Prevnar recipients. Based on limited data, responses to mumps and rubella
antigens in Prevnar 13 recipients were similar to those in Prevnar recipients.
Adults ≥50 Years of Age
Concomitant Administration with QI V
Prevnar 13 was administered to PPSV23 previously vaccinated adults ≥50 y ears of age
concomitantly with a U S-licensed inactivated influenza vaccine ,quadrivalent (IIV4) (Fluzone
Quadrivalent) for the 2014/2015 influenza season (Study 13) [see Adverse Reactions (6.2) and
Drug Interactions (7.1) ]. Onestudy group received Prevnar 13 and IIV4concurrentl y, followed
approximately one month later by placebo .A second study group received IIV 4and placebo
concur rently , followed approximately one month later by Prevnar 13.
Seroty pe-specific pneumococcal a ntibody responses were measured one month after Prevnar 13
vaccination as OPA GMTs. Noninferiorit y was demonstrated for each pneumococcal serot ype if
the lower l imit of the 2- sided 95% CI for the GMT ratio ( Prevnar 13 + I IV4 relative to Prevnar
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4213 alone) was > 0.5.Although OPA antibody responses to Prevnar 13 generally appeared to be
slightly lower when Prevnar 13 was administered concomitantly with IIV 4compared to Prevnar
13 administered alone , noninferiority was demonstrated for all Prevnar 13 pneumococcal
seroty pes evaluated in S tudy 13.
Strain -specific influenza antibody responses were measured one month after IIV4 as
hemagglutinin inhibition assay (HAI) tit ers. HAI GMTs were evaluated for each IIV4 strain in
Study 13. Noninferiority was demonstrated if the lower limit of the 2 -sided 95% CI for the HAI
GMT ratio (Prevnar 13 + IIV4 re lative to IIV4 + Placebo) was > 0.5. Noninferiority was
demonstrated for each IIV4 vaccine strain evaluated in Study 13.
Concomitant Administration with TI V
Two randomized, double-blind clinical trials evaluated the immunogenicity of Prevnar 13 given
with IIV3 (Fall 2007/ Spring 2008 Fluarix, A/H1N1, A/H3N2, and B strains) in PPSV23
unvaccinated adults aged 50 through 59 years10(Study 10, conducted in the US) and in adults
≥65 y ears11(Study 11, conducted in Europe). Based on anal ysis of the primary pre-specified
comparison of seroty pe specific anti -capsular polysaccharide IgG GMCs,noninferiority was met
for all serot ypes in adults 50- 59 years of age and for 12 of 13 serotypes in adults ≥65y ears of
age.
15 REFERENCES
ClinicalTrials.gov identifie rs for studies included below:
1.Study 1 NCT00205803
2.Study 2 NCT00373958
3.Study 3 NCT00444457
4.Study 4 NCT00452452
5.Study 5 NCT00761631
6.Study 6 NCT00427895
7.Study 7 NCT00546572
8.Study 8 NCT00574548
9.Study 9 NCT00500266
10.Study 10 NCT00521586
11.Study 11
NCT00492557
12.Study 12 NCT00744263
13.Study 13 NCT02124161
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4316 HOW SUPPLIED/STORAGE AND HANDLING
Prefille d Syringe, 1 Dose (10 per package) – NDC 0005-1971-02.
Prefilled Sy ringe, 1 Dose (1 per package) – NDC 0005-1971-05.
After shipping, Prevnar 13 may arrive at temperatures between 2ºC to 25ºC (36ºF to 77ºF ).
Upon receipt , store refrigerated at 2ºC to 8ºC (36ºF to 46ºF).
Do not freeze. Discard if the vaccine has been frozen.
Prevnar 13 is stable at temperatures up to 25 ºC (77 ºF) for 4 days. These data are not
recommendations for shipping or storage, but may guide decisions for use in case of temporary
temperature excursions.
The tip cap and rubber plunger of the prefilled s yringe are not made with natural rubber latex.
17 PATIENT COUNSELING INFORMATION
Prior to administration of this vaccine, inform the individual, parent, guardian, or other
responsible adult of the following:
The potential benefits and risks of immunization with Prevnar 13 [see Warnings and
Precautions (5) and Adverse Reactions (6 )].
Theimportance of completing the immunization series unless contraindicated.
Any suspected adverse reactions should be reported to their healthcare professional.
Provide the Vaccine Information Statements, which are available free of charge at the Centers
for Disease Control and Prevention (CDC) website ( www.cdc.gov/vaccines).
This product’s label may have been updated. For current full prescribing information, please visit
www.pfizer.com .
US Govt. L icense No. 3
LAB -0469-1 8.0
CPT Code 90670
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