PREVENAR 13 CONJUGATED POLYSACCHARIDE PNEUMOCOCCAL VACCINE (13-VALENT ADSORBED) suspension for injection in pre-filled syringe medication leaflet

Prevenar 13 suspension for injectionpneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)

1 dose (0.5 ml) contains:

Pneumococcal polysaccharide serotype 11 2.2 µg

Pneumococcal polysaccharide serotype 31 2.2 µg

Pneumococcal polysaccharide serotype 41 2.2 µg

Pneumococcal polysaccharide serotype 51 2.2 µg

Pneumococcal polysaccharide serotype 6A1 2.2 µg

Pneumococcal polysaccharide serotype 6B1 4.4 µg

Pneumococcal polysaccharide serotype 7F1 2.2 µg

Pneumococcal polysaccharide serotype 9V1 2.2 µg

Pneumococcal polysaccharide serotype 141 2.2 µg

Pneumococcal polysaccharide serotype 18C1 2.2 µg

Pneumococcal polysaccharide serotype 19A1 2.2 µg

Pneumococcal polysaccharide serotype 19F1 2.2 µg

Pneumococcal polysaccharide serotype 23F1 2.2 µg1Conjugated to CRM197 carrier protein, adsorbed on aluminium phosphate.

1 dose (0.5 ml) contains approximately 32 µg CRM197 carrier protein and 0.125 mg aluminium.

For the full list of excipients, see section 6.1.

Suspension for injection.

The vaccine is a homogeneous white suspension.

Active immunisation for the prevention of invasive disease, pneumonia and acute otitis media causedby Streptococcus pneumoniae in infants, children and adolescents from 6 weeks to 17 years of age.

Active immunisation for the prevention of invasive disease and pneumonia caused by Streptococcuspneumoniae in adults ≥18 years of age and the elderly.

See sections 4.4 and 5.1 for information on protection against specific pneumococcal serotypes.

The use of Prevenar 13 should be determined on the basis of official recommendations taking intoconsideration the risk of invasive disease and pneumonia in different age groups, underlyingcomorbidities as well as the variability of serotype epidemiology in different geographical areas.

The immunisation schedules for Prevenar 13 should be based on official recommendations.

Infants and children aged 6 weeks to 5 years

It is recommended that infants who receive a first dose of Prevenar 13 complete the vaccination coursewith Prevenar 13.

Infants aged 6 weeks-6 months

Three-dose primary series

The recommended immunisation series consists of four doses, each of 0.5 ml. The primary infantseries consists of three doses, with the first dose usually given at 2 months of age and with an intervalof at least 1 month between doses. The first dose may be given as early as six weeks of age. The fourth(booster) dose is recommended between 11 and 15 months of age.

Two-dose primary series

Alternatively, when Prevenar 13 is given as part of a routine infant immunisation programme, a seriesconsisting of three doses, each of 0.5 ml, may be given. The first dose may be administered from theage of 2 months, with a second dose 2 months later. The third (booster) dose is recommended between11 and 15 months of age (see section 5.1).

Preterm infants (<37 weeks gestation)

In preterm infants, the recommended immunisation series consists of four doses, each of 0.5 ml. Theprimary infant series consists of three doses, with the first dose given at 2 months of age and with aninterval of at least 1 month between doses. The first dose may be given as early as six weeks of age.

The fourth (booster) dose is recommended between 11 and 15 months of age (see sections 4.4 and5.1).

Unvaccinated infants and children ≥ 7 months of age

Infants aged 7-11 months

Two doses, each of 0.5 ml, with an interval of at least 1 month between doses. A third dose isrecommended in the second year of life.

Children aged 12-23 months

Two doses, each of 0.5 ml, with an interval of at least 2 months between doses (see section 5.1).

Children and adolescents aged 2-17 years

One single dose of 0.5 ml.

Prevenar 13 vaccine schedule for infants and children previously vaccinated with Prevenar (7-valent)(Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F)

Prevenar 13 contains the same 7 serotypes included in Prevenar, using the same carrier protein

CRM197.

Infants and children who have begun immunisation with Prevenar may switch to Prevenar 13 at anypoint in the schedule.

Young children (12-59 months) completely immunised with Prevenar (7-valent)

Young children who are considered completely immunised with Prevenar (7-valent) should receiveone dose of 0.5 ml of Prevenar 13 to elicit immune responses to the 6 additional serotypes. This doseof Prevenar 13 should be administered at least 8 weeks after the final dose of Prevenar (7-valent) (seesection 5.1).

Children and adolescents 5-17 years

Children 5 to 17 years of age may receive a single dose of Prevenar 13 if they have been previouslyvaccinated with one or more doses of Prevenar. This dose of Prevenar 13 should be administered atleast 8 weeks after the final dose of Prevenar (7-valent) (see section 5.1).

Adults ≥18 years of age, and the elderly

One single dose.

The need for revaccination with a subsequent dose of Prevenar 13 has not been established.

Regardless of prior pneumococcal vaccination status, if the use of 23-valent pneumococcalpolysaccharide vaccine is considered appropriate, Prevenar 13 should be given first (see sections 4.5and 5.1).

Individuals who have underlying conditions predisposing them to invasive pneumococcal disease(such as sickle cell disease or HIV infection) including those previously vaccinated with one or moredoses of 23-valent pneumococcal polysaccharide vaccine may receive at least one dose of Prevenar 13(see section 5.1).

In individuals with an haematopoietic stem cell transplant (HSCT), the recommended immunisationseries consists of four doses of Prevenar 13, each of 0.5 ml. The primary series consists of three doses,with the first dose given at 3 to 6 months after HSCT and with an interval of at least 1 month betweendoses. A fourth (booster) dose is recommended 6 months after the third dose (see section 5.1).

The vaccine should be given by intramuscular injection. The preferred sites are the anterolateral aspectof the thigh (vastus lateralis muscle) in infants or the deltoid muscle of the upper arm in children andadults.

Hypersensitivity to the active substances, to any of the excipients listed in section 6.1, or to diphtheriatoxoid.

As with other vaccines, the administration of Prevenar 13 should be postponed in subjects sufferingfrom acute, severe febrile illness. However, the presence of a minor infection, such as a cold, shouldnot result in the deferral of vaccination.

Prevenar 13 must not be administered intravascularly.

As with all injectable vaccines, appropriate medical treatment and supervision should always bereadily available in case of a rare anaphylactic event following the administration of the vaccine.

This vaccine should not be given as an intramuscular injection to individuals with thrombocytopaeniaor any coagulation disorder that would contraindicate intramuscular injection, but may be givensubcutaneously if the potential benefit clearly outweighs the risks (see section 5.1).

Prevenar 13 will only protect against Streptococcus pneumoniae serotypes included in the vaccine, andwill not protect against other microorganisms that cause invasive disease, pneumonia, or otitis media.

As with any vaccine, Prevenar 13 may not protect all individuals receiving the vaccine frompneumococcal disease. For the most recent epidemiological information in your country you shouldconsult with the relevant national organisation.

Individuals with impaired immune responsiveness, whether due to the use of immuno-suppressivetherapy, a genetic defect, human immunodeficiency virus (HIV) infection, or other causes, may havereduced antibody response to active immunisation.

Safety and immunogenicity data are available for a limited number of individuals with sickle celldisease, HIV infection, or with an haematopoietic stem cell transplant (see section 5.1). Safety andimmunogenicity data for Prevenar 13 are not available for individuals in other specificimmuno-compromised groups (e.g., malignancy or nephrotic syndrome) and vaccination should beconsidered on an individual basis.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially‘sodium-free’.

Infants and children aged 6 weeks to 5 years

In clinical studies, Prevenar 13 elicited an immune response to all thirteen serotypes included in thevaccine. The immune response for serotype 3 following the booster dose was not increased above thelevels seen after the infant vaccination series; the clinical relevance of this observation regarding theinduction of serotype 3 immune memory is unknown (see section 5.1).

The proportions of functional antibody responders (OPA titres ≥ 1:8) to serotypes 1, 3 and 5 werehigh. However, the OPA geometric mean titres were lower than those against each of the remainingadditional vaccine serotypes; the clinical relevance of this observation for protective efficacy isunknown (see section 5.1).

Limited data have demonstrated that Prevenar 7-valent (three-dose primary series) induces anacceptable immune response in infants with sickle cell disease with a safety profile similar to thatobserved in non-high-risk groups (see section 5.1).

Children younger than 2 years old should receive the appropriate-for-age Prevenar 13 vaccinationseries (see section 4.2). The use of pneumococcal conjugate vaccine does not replace the use of23-valent pneumococcal polysaccharide vaccines in children ≥ 2 years of age with conditions (such assickle cell disease, asplenia, HIV infection, chronic illness, or those who are immuno-compromised)placing them at higher risk for invasive disease due to Streptococcus pneumoniae. Wheneverrecommended, children at risk who are ≥ 24 months of age and already primed with Prevenar 13should receive 23-valent pneumococcal polysaccharide vaccine. The interval between the 13-valentpneumococcal conjugate vaccine (Prevenar 13) and the 23-valent pneumococcal polysaccharidevaccine should not be less than 8 weeks. There are no data available to indicate whether theadministration of 23-valent pneumococcal polysaccharide vaccine to unprimed children or to childrenprimed with Prevenar 13 might result in hyporesponsiveness to further doses of Prevenar 13.

The potential risk of apnoea and the need for respiratory monitoring for 48-72 h should be consideredwhen administering the primary immunisation series to very premature infants (born  28 weeks ofgestation), and particularly for those with a previous history of respiratory immaturity. As the benefitof vaccination is high in this group of infants, vaccination should not be withheld or delayed.

For vaccine serotypes, protection against otitis media is expected to be lower than protection againstinvasive disease. As otitis media is caused by many organisms other than pneumococcal serotypesrepresented in the vaccine, protection against all otitis media is expected to be low (see section 5.1).

When Prevenar 13 is administered concomitantly with Infanrix hexa (DTPa-HBV-IPV/Hib), the ratesof febrile reactions are similar to those seen with concomitant administration of Prevenar(7-valent) and Infanrix hexa (see section 4.8). Increased reporting rates of convulsions (with or withoutfever) and hypotonic hyporesponsive episode (HHE) were observed with concomitant administrationof Prevenar 13 and Infanrix hexa (see section 4.8).

Antipyretic treatment should be initiated according to local treatment guidelines for children withseizure disorders or with a prior history of febrile seizures and for all children receiving Prevenar 13simultaneously with vaccines containing whole cell pertussis.

Infants and children aged 6 weeks to 5 years

Prevenar 13 can be given concomitantly with any of the following vaccine antigens, either asmonovalent or combination vaccines: diphtheria, tetanus, acellular or whole cell pertussis,

Haemophilus influenzae type b, inactivated poliomyelitis, hepatitis B (see section 4.4 for guidance on

Infanrix hexa), meningococcal serogroup C, measles, mumps, rubella, varicella and rotavirus vaccine.

Prevenar 13 can also be given concomitantly between 12-23 months with the tetanus toxoidconjugated meningococcal polysaccharide serogroups A, C, W and Y vaccine to children who havebeen adequately primed with Prevenar 13 (as per local recommendations).

Data from a postmarketing clinical study evaluating the impact of prophylactic use of antipyretics(ibuprofen and paracetamol) on the immune response to Prevenar 13 suggest that administration ofparacetamol concomitantly or within the same day of vaccination may reduce the immune response to

Prevenar 13 after the infant series. Responses to the booster dose administered at 12 months wereunaffected. The clinical significance of this observation is unknown.

Children and adolescents 6 to 17 years of age

No data are currently available regarding concomitant use with other vaccines.

Adults 18 to 49 years of age

No data are available regarding concomitant use with other vaccines.

Adults aged 50 years and older

Prevenar 13 may be administered concomitantly with the seasonal trivalent inactivated influenzavaccine (TIV).

In two studies conducted in adults aged 50-59 and 65 years and older, it was demonstrated that

Prevenar 13 may be given concomitantly with trivalent inactivated influenza vaccine (TIV). Theresponses to all three TIV antigens were comparable when TIV was given alone or concomitantly with

Prevenar 13.

When Prevenar 13 was given concomitantly with TIV, the immune responses to Prevenar 13 werelower compared to when Prevenar 13 was given alone, however, there was no long-term impact oncirculating antibody levels.

In a third study in adults aged 50-93 years, it was demonstrated that Prevenar 13 may be givenconcomitantly with the seasonal quadrivalent inactivated influenza vaccine (QIV). The immuneresponses to all four QIV strains were noninferior when Prevenar 13 was given concomitantly with

QIV compared to when QIV was given alone.

The immune responses to Prevenar 13 were noninferior when Prevenar 13 was given concomitantlywith QIV compared to when Prevenar 13 was given alone. As with concomitant administration withtrivalent vaccines, immune responses to some pneumococcal serotypes were lower when both vaccineswere given concomitantly.

Concomitant use with other vaccines has not been investigated.

Different injectable vaccines should always be given at different vaccination sites.

Concomitant administration of Prevenar 13 and 23-valent pneumococcal polysaccharide vaccine hasnot been studied. In clinical studies when Prevenar 13 was given 1 year after 23-valent pneumococcalpolysaccharide vaccine the immune responses were lower for all serotypes compared to when

Prevenar 13 was given to subjects not previously immunised with 23-valent pneumococcalpolysaccharide vaccine. The clinical significance of this is unknown.

There are no data from the use of pneumococcal 13-valent conjugate vaccine in pregnant women.

Therefore the use of Prevenar 13 should be avoided during pregnancy.

It is unknown whether pneumococcal 13-valent conjugate vaccine is excreted in human milk.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

Prevenar 13 has no or negligible influence on the ability to drive and use machines. However, some ofthe effects mentioned under section 4.8 “Undesirable effects” may temporarily affect the ability todrive or use machines.

Analysis of postmarketing reporting rates suggests a potential increased risk of convulsions, with orwithout fever, and HHE when comparing groups which reported use of Prevenar 13 with Infanrix hexato those which reported use of Prevenar 13 alone.

Adverse reactions reported in clinical studies or from the postmarketing experience for all age groupsare listed in this section per system organ class, in decreasing order of frequency and seriousness. Thefrequency is defined as follows: very common ( 1/10), common ( 1/100 to < 1/10), uncommon( 1/1,000 to < 1/100), rare ( 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot beestimated from available data).

Infants and children aged 6 weeks to 5 years

The safety of the vaccine was assessed in controlled clinical studies where 14,267 doses were given to4,429 healthy infants from 6 weeks of age at first vaccination and 11-16 months of age at booster dose.

In all infant studies, Prevenar 13 was co-administered with routine paediatric vaccines (see section4.5).

Safety in 354 previously unvaccinated children (7 months to 5 years of age) was also assessed.

The most commonly reported adverse reactions in children 6 weeks to 5 years of age werevaccination-site reactions, fever, irritability, decreased appetite, and increased and/or decreased sleep.

In a clinical study in infants vaccinated at 2, 3, and 4 months of age, fever ≥ 38°C was reported athigher rates among infants who received Prevenar (7-valent) concomitantly with Infanrix hexa (28.3%to 42.3%) than in infants receiving Infanrix hexa alone (15.6% to 23.1%). After a booster dose at 12 to15 months of age, fever ≥ 38°C was reported in 50.0% of infants who received Prevenar (7-valent) and

Infanrix hexa at the same time as compared to 33.6% of infants receiving Infanrix hexa alone. Thesereactions were mostly moderate (less than or equal to 39°C) and transient.

An increase in vaccination-site reactions was reported in children older than 12 months compared torates observed in infants during the primary series with Prevenar 13.

Adverse reactions from clinical studies

In clinical studies, the safety profile of Prevenar 13 was similar to Prevenar. The following frequenciesare based on adverse reactions assessed in Prevenar 13 clinical studies:

Rare: Hypersensitivity reaction including face oedema, dyspnoea, bronchospasm

Uncommon: Convulsions (including febrile convulsions)

Rare: Hypotonic-hyporesponsive episode

Very common: Decreased appetite

Common: Vomiting; diarrhoea

Common: Rash

Uncommon: Urticaria or urticaria-like rash

Very common: Pyrexia; irritability; any vaccination-site erythema, induration/swelling orpain/tenderness; somnolence; poor quality sleep

Vaccination-site erythema or induration/swelling 2.5 cm-7.0 cm (after thebooster dose and in older children [age 2 to 5 years])

Common: Pyrexia > 39°C; vaccination-site movement impairment (due to pain);vaccination-site erythema or induration/swelling 2.5 cm-7.0 cm (after infantseries)

Uncommon: Vaccination-site erythema, induration/swelling > 7.0 cm; crying

Additional information in special populations:

Apnoea in very premature infants ( 28 weeks of gestation) (see section 4.4).

Children and adolescents aged 6 to 17 years of age

Safety was evaluated in 592 children (294 children aged 5 to 10 years previously immunised with atleast one dose of Prevenar and 298 children aged 10 to 17 years who had not received a pneumococcalvaccine).

The most common adverse events in children and adolescents 6 to 17 years of age were:

Common: Headaches

Very common: Decreased appetite

Common: Vomiting; diarrhoea

Common: Rash; urticaria or urticaria-like rash

Very common: Irritability; any vaccination-site erythema; induration/swelling orpain/tenderness; somnolence; poor quality sleep;vaccination-site tenderness (including impaired movement)

Common: Pyrexia

Other adverse events previously observed in infants and children 6 weeks to 5 years of age may alsobe applicable to this age group but were not seen in this study possibly due to the small sample size.

Additional information in special populations

Children and adolescents with sickle cell disease, HIV infection, or an haematopoietic stem celltransplant have similar frequencies of adverse reactions, except that headaches, vomiting, diarrhoea,pyrexia, fatigue, arthralgia, and myalgia were very common.

Adults ≥ 18 years and the elderly

Safety was assessed in 7 clinical studies including 91,593 adults ranging in age from 18 to 101 years.

Prevenar 13 was administered to 48,806 adults; 2,616 (5.4%) aged 50 to 64 years, and 45,291 (92.8%)aged 65 years and older. One of the 7 studies included a group of adults (n=899) ranging from 18 to 49years who received Prevenar 13 and who were not previously vaccinated with 23-valent pneumococcalpolysaccharide vaccine. Of the Prevenar 13 recipients 1,916 adults were previously vaccinated withthe 23-valent pneumococcal polysaccharide vaccine at least 3 years prior to study vaccination, and46,890 were 23-valent pneumococcal polysaccharide vaccine unvaccinated.

A trend to lower frequency of adverse reactions was associated with greater age; adults > 65 years ofage (regardless of prior pneumococcal vaccination status) reported fewer adverse reactions thanyounger adults, with adverse reactions generally most common in the youngest adults, 18 to 29 yearsof age.

Overall, the frequency categories were similar for all age groups, with the exception of vomiting whichwas very common ( 1/10) in adults aged 18 to 49 years and common ( 1/100 to < 1/10) in all otherage groups, and pyrexia was very common in adults aged 18 to 29 years and common in all other agegroups. Severe vaccination-site pain/tenderness and severe limitation of arm movement was verycommon in adults 18 to 39 years and common in all other age groups.

Adverse reactions from clinical studies

Local reactions and systemic events were solicited daily after each vaccination for 14 days in 6 studiesand 7 days in the remaining study. The following frequencies are based on adverse reactions assessedin Prevenar 13 clinical studies in adults:

Very common: Decreased appetite

Very common: Headaches

Very common: Diarrhoea; vomiting (in adults aged 18 to 49 years)

Common: Vomiting (in adults aged 50 years and over)

Uncommon: Nausea

Uncommon: Hypersensitivity reaction including face oedema, dyspnoea, bronchospasm

Very common: Rash

Very common: Chills; fatigue; vaccination-site erythema; vaccination-siteinduration/swelling; vaccination-site pain/tenderness (severe vaccination-sitepain/tenderness very common in adults aged 18 to 39 years); limitation of armmovement (severe limitation of arm movements very common in adults aged18 to 39 years)

Common: Pyrexia (very common in adults aged 18 to 29 years)

Uncommon: Lymphadenopathy localized to the region of the vaccination-site

Very common: Arthralgia; myalgia

Overall, no significant differences in frequencies of adverse reactions were seen when Prevenar 13 wasgiven to adults previously vaccinated with the pneumococcal polysaccharide vaccine.

Additional information in special populations

Adults with HIV infection have similar frequencies of adverse reactions, except that pyrexia andvomiting were very common and nausea common.

Adults with an haematopoietic stem cell transplant have similar frequencies of adverse reactions,except that pyrexia and vomiting were very common.

Higher frequency in some solicited systemic reactions was observed when Prevenar 13 wasadministered concomitantly with trivalent inactivated influenza vaccine (TIV) compared to TIV givenalone (headache, chills, rash, decreased appetite, arthralgia, and myalgia) or Prevenar 13 given alone(headache, fatigue, chills, decreased appetite, and arthralgia).

Adverse reactions from Prevenar 13 postmarketing experience

The following are considered adverse drug reactions for Prevenar 13; because these reactions werederived from spontaneous reports, the frequencies could not be determined and are thus considered asnot known.

Lymphadenopathy (localised to the region of the vaccination-site)

Anaphylactic/anaphylactoid reaction including shock; angioedema

Erythema multiforme

Vaccination-site urticaria; vaccination-site dermatitis; vaccination-sitepruritus; flushing

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose with Prevenar 13 is unlikely due to its presentation as a pre-filled syringe. However, ininfants and children there have been reports of overdose with Prevenar 13 defined as subsequent dosesadministered closer than recommended to the previous dose. In general, adverse events reported withoverdose are consistent with those that have been reported with doses given in the recommendedpaediatric schedules of Prevenar 13.

Pharmacotherapeutic group: vaccines, pneumococcal vaccines; ATC code: J07AL02

Prevenar 13 contains the 7 pneumococcal capsular polysaccharides that are in Prevenar (4, 6B, 9V, 14,18C, 19F, 23F) plus 6 additional polysaccharides (1, 3, 5, 6A, 7F, 19A) all conjugated to CRM197carrier protein.

Burden of disease

Infants and children aged 6 weeks to 5 years

Based on serotype surveillance in Europe performed before the introduction of Prevenar, Prevenar 13is estimated to cover 73-100% (depending on the country) of serotypes causing invasive pneumococcaldisease (IPD) in children less than 5 years of age. In this age group, serotypes 1, 3, 5, 6A, 7F, and 19Aaccount for 15.6% to 59.7% of invasive disease, depending on the country, the time period studied,and the use of Prevenar.

Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can beresponsible for 60-70% of clinical episodes of AOM. S. pneumoniae is one of the most commoncauses of bacterial AOM worldwide.

Prevenar 13 is estimated to cover over 90% of serotypes causing antimicrobial-resistant IPD.

Children and adolescents aged 6 to 17 years

In children and adolescents aged 6 to 17 years, the incidence of pneumococcal disease is low,however, there is an increased risk of morbidity and mortality in those with underlying comorbidities.

Adults ≥18 years and the elderly

Pneumonia is the most common clinical presentation of pneumococcal disease in adults.

The reported incidence of community-acquired pneumonia (CAP) and IPD in Europe varies bycountry, increases with age from 50 years and is highest in individuals aged ≥ 65 years. S. pneumoniaeis the most frequent cause of CAP, and is estimated to be responsible for approximately 30% of all

CAP cases requiring hospitalisation in adults in developed countries.

Bacteraemic pneumonia (approximately 80% of IPD in adults), bacteraemia without a focus, andmeningitis are the most common manifestations of IPD in adults. Based on surveillance data followingthe introduction of Prevenar but before the introduction of Prevenar 13 in childhood vaccinationprogrammes, the pneumococcal serotypes in Prevenar 13 may be responsible for at least 50 - 76%(depending on country) of IPD in adults.

The risk for CAP and IPD in adults also increases with chronic underlying medical conditions,specifically, anatomical or functional asplenia, diabetes mellitus, asthma, chronic cardiovascular,pulmonary, kidney or liver disease, and it is highest in those who are immune-suppressed such as thosewith malignant haematological diseases or HIV infection.

Prevenar 13 immunogenicity clinical studies in infants, children and adolescents

The protective efficacy of Prevenar 13 against IPD has not been studied. As recommended by the

World Health Organization (WHO) the assessment of potential efficacy against IPD in infants andyoung children has been based on a comparison of immune responses to the seven common serotypesshared between Prevenar 13 and Prevenar, for which protective efficacy has been proven (for Prevenar(7-valent) efficacy in infants and children, see below). Immune responses to the additional 6 serotypeswere also measured.

Immune responses following a three-dose primary infant series

Clinical studies have been conducted in a number of European countries and the US using a range ofvaccination schedules, including two randomised non-inferiority studies (Germany using a 2, 3,4 month primary series [006] and US using a 2, 4, 6 month primary series [004]). In these two studiespneumococcal immune responses were compared using a set of non-inferiority criteria including thepercentage of subjects with serum anti-polysaccharide serotype-specific IgG ≥ 0.35 μg/ml one monthafter the primary series and the comparison of IgG geometric mean concentrations (ELISA GMCs); inaddition, functional antibody titres (OPA) between subjects receiving Prevenar 13 and Prevenar werecompared. For the six additional serotypes, these values were compared with the lowest responseamong all of the seven common serotypes in the Prevenar recipients.

The non-inferiority immune response comparisons for study 006, based on the proportion of infantsachieving anti-polysaccharide IgG concentrations ≥ 0.35 μg/ml, are shown in Table 1. Results forstudy 004 were similar. Prevenar 13 non-inferiority (lower bound of the 95% CI for the difference inpercentage of responders at 0.35 µg/ml between groups was >-10%) was demonstrated for all7 common serotypes, except for serotype 6B in study 006 and serotypes 6B and 9V in study 004,which missed by a small margin. All seven common serotypes met pre-defined non-inferiority criteriafor IgG ELISA GMCs. Prevenar 13 elicited comparable, although slightly lower, antibody levels than

Prevenar for the 7 common serotypes. The clinical relevance of these differences is not known.

Non-inferiority was met for the 6 additional serotypes based on the proportion of infants achievingantibody concentrations ≥ 0.35 μg/ml and comparison of IgG ELISA GMCs in study 006 and was metfor 5 out of the 6 serotypes, with the exception of serotype 3 for study 004. For serotype 3, thepercentages of Prevenar 13 recipients with serum IgG ≥ 0.35 μg/ml were 98.2% (study 006) and63.5% (study 004).

Table 1: Comparison of the proportion of subjects achieving a pneumococcal anti-polysaccharide IgGantibody concentration ≥ 0.35 μg/ml after dose 3 of the infant series - study 006

Prevenar 13 7-valent Prevenar% % Difference

Serotypes(N=282-285) (N=277-279) (95 % CI)7-valent Prevenar serotypes4 98.2 98.2 0.0 (-2.5, 2.6)6B 77.5 87.1 -9.6 (-16.0, -3.3)9V 98.6 96.4 2.2 (-0.4, pct. 5.2)14 98.9 97.5 1.5 (-0.9, 4.1)18C 97.2 98.6 -1.4 (-4.2, 1.2)19F 95.8 96.0 -0.3 (-3.8, 3.3)23F 88.7 89.5 -0.8 (-6.0, 4.5)

Additional serotypes in Prevenar 131 96.1 87.1* 9.1 (4.5, 13.9)3 98.2 87.1 11.2 (7.0, 15.8)5 93.0 87.1 5.9 (0.8, 11.1)6A 91.9 87.1 4.8 (-0.3, 10.1)7F 98.6 87.1 11.5 (7.4, 16.1)19A 99.3 87.1 12.2 (8.3, 16.8)

* The serotype in Prevenar with the lowest percent response rate was 6B in study 006 (87.1 %).

Prevenar 13 elicited functional antibodies to all 13 vaccine serotypes in studies 004 and 006. For the7 common serotypes there were no differences between groups in the proportion of subjects with OPAtitres ≥ 1:8. For each of the seven common serotypes, > 96% and >90 % of the Prevenar 13 recipientsreached an OPA titre ≥ 1:8 one month after the primary series in studies 006 and 004, respectively.

For each of the 6 additional serotypes, Prevenar 13 elicited OPA titres ≥ 1:8 in 91.4% to 100% ofvaccinees one month after the primary series in studies 004/006. The functional antibody (OPA)geometric mean titres for serotypes 1, 3 and 5 were lower than the titres for each of the otheradditional serotypes; the clinical relevance of this observation for protective efficacy is unknown.

Immune responses following a two-dose primary infant series

The immunogenicity after two doses in infants has been documented in four studies. The proportion ofinfants achieving a pneumococcal anti-capsular polysaccharide IgG concentration ≥ 0.35 g/ml onemonth after the second dose ranged from 79.6% to 98.5% across 11 of the 13 vaccine serotypes.

Smaller proportions of infants achieved this antibody concentration threshold for serotype 6B (27.9%to 57.3%) and 23F (55.8% to 68.1%) for all studies using a 2, 4 month regimen, compared to 58.4%for serotype 6B and 68.6% for 23F for a study using a 3, 5 month regimen. After the booster dose, allvaccine serotypes including 6B and 23F had immune responses consistent with adequate priming witha two-dose primary series. In a UK study, the functional antibody (OPA) responses were comparablefor all serotypes including 6B and 23F in the Prevenar and Prevenar 13 arms after the primary series attwo and four months of age and after the booster dose at 12 months of age. For Prevenar 13 recipients,the proportion of responders with an OPA titre  1:8 was at least 87 % following the infant series, andat least 93% following the booster dose. The OPA geometric mean titres for serotypes 1, 3 and 5 werelower than the titres for each of the other additional serotypes; the clinical relevance of thisobservation is unknown.

Booster responses following two-dose and three-dose primary infant series

Following the booster dose, antibody concentrations increased from the pre-booster level for all 13serotypes. Post-booster antibody concentrations were higher for 12 serotypes than those achieved afterthe infant primary series. These observations are consistent with adequate priming (the induction ofimmunologic memory). The immune response for serotype 3 following the booster dose was notincreased above the levels seen after the infant vaccination series; the clinical relevance of thisobservation regarding the induction of serotype 3 immune memory is unknown.

Antibody responses to booster doses following two-dose or three-dose infant primary series werecomparable for all 13 vaccine serotypes.

For children aged from 7 months to 5 years, age appropriate catch-up immunisation schedules (asdescribed in section 4.2) result in levels of anti-capsular polysaccharide IgG antibody responses toeach of the 13 serotypes that are at least comparable to those of a three-dose primary series in infants.

Antibody persistence and immunological memory were evaluated in a study in healthy children whoreceived a single dose of Prevenar 13 at least 2 years after they had been previously immunised witheither 4 doses of Prevenar, a 3-dose infant series of Prevenar followed by Prevenar 13 at 12 months ofage, or 4 doses of Prevenar 13.

The single dose of Prevenar 13, in children approximately 3.4 years of age regardless of previousvaccination history with Prevenar or Prevenar 13, induced a robust antibody response for both the7 common serotypes and the 6 additional serotypes in Prevenar 13.

Since the introduction of 7-valent Prevenar in 2000, pneumococcal disease surveillance data have notshown that the immunity elicited by Prevenar in infancy has waned over time.

Preterm Infants

Safety and immunogenicity of Prevenar 13 given at 2, 3, 4 and 12 months was assessed inapproximately 100 prematurely born infants (mean Estimated Gestational Age [EGA], 31 weeks;range, 26 to 36 weeks) and compared with approximately 100 infants born at term (mean EGA,39 weeks; range, 37 to 42 weeks).

Immune responses in preterm and term infants were compared using the proportion of subjectsachieving a pneumococcal polysaccharide IgG binding antibody concentration ≥0.35 μg/mL 1 monthafter the infant series, the approach used for immunogenicity comparisons of Prevenar 13 to Prevenarbased on WHO guidelines.

More than 85% achieved a pneumococcal polysaccharide IgG binding antibody concentration≥0.35 µg/mL 1 month after the infant series, except for serotypes 5 (71.7%), 6A (82.7%), and 6B(72.7%) in the preterm group. For these 3 serotypes, the proportion of responders among preterminfants was significantly lower than among term infants. Approximately one month after the toddlerdose, the proportion of subjects in each group achieving this same antibody concentration thresholdwas >97%, except for serotype 3 (71% in preterm infants and 79% in term infants). It is unknownwhether immunological memory to all serotypes is induced in pre-term infants. In general,serotype-specific IgG GMCs were lower for preterm infants than term infants.

After the infant series, OPA GMTs were similar in preterm infants compared to term infants except forserotype 5, which was lower in preterm infants. OPA GMTs after the toddler dose relative to thoseafter the infant series were similar or lower for 4 serotypes (4, 14, 18C, and 19F) and were statisticallysignificantly higher for 6 of 13 serotypes (1, 3, 5, 7F, 9V, and 19A) in preterm infants compared to 10of 13 serotypes (1, 3, 4, 5, 6A, 7F, 9V, 18C, 19A, and 23F) in term infants.

Children (12-59 months) completely immunised with Prevenar (7-valent)

Following administration of a single dose of Prevenar 13 to children (12-59 months) who areconsidered completely immunised with Prevenar (7-valent) (either 2 or 3 dose primary series plusbooster), the proportion achieving serum IgG levels ≥0.35 µg/ml and OPA titres ≥1:8 was at least90%. However, 3 (serotypes 1, 5 and 6A) of the 6 additional serotypes showed lower IgG GMC and

OPA GMT when compared with children who had received at least one previous vaccination with

Prevenar 13. The clinical relevance of the lower GMCs and GMTs is currently unknown.

Unvaccinated Children (12-23 months)

Studies in unvaccinated children (12-23 months) with Prevenar (7-valent) demonstrated that 2 doseswere required to achieve serum IgG concentrations for 6B and 23F similar to those induced by a3-dose infant series.

Children and Adolescents 5 to 17 years of age

In an open-label study in 592 healthy children and adolescents including those with asthma (17.4%)who may be predisposed to pneumococcal infection, Prevenar 13 elicited immune responses to all13 serotypes. A single dose of Prevenar 13 was given to children 5 to 10 years of age previouslyvaccinated with at least 1 dose of Prevenar, and children and adolescents 10 to 17 years of age whohad never received a pneumococcal vaccine.

In both the children 5 to 10 years of age and children and adolescents aged 10 to 17 years, the immuneresponse to Prevenar 13 was non inferior to Prevenar for the 7 common serotypes and to Prevenar 13for the 6 additional serotypes compared to the immune response after the fourth dose in infantsvaccinated at 2, 4, 6 and 12-15 months of age as measured by serum IgG.

In children and adolescents aged 10 to 17 years of age OPA GMTs 1 month after vaccination werenoninferior to OPA GMTs in the 5 to 10 year old age group for 12 of the 13 serotypes (exceptserotype 3).

Immune responses after subcutaneous administration

Subcutaneous administration of Prevenar 13 was evaluated in a non-comparative study in 185 healthy

Japanese infants and children who received 4 doses at 2, 4, 6 and 12-15 months of age. The studydemonstrated that safety and immunogenicity were generally comparable with observations made instudies of intramuscular administration.

Prevenar 13 Effectiveness

Invasive Pneumococcal Disease

Data published by Public Health England showed that, four years after the introduction of Prevenar asa two dose primary infant series with booster dose in the second year of life and with a 94% vaccineuptake, there was a 98% (95% CI 95; 99) reduction in disease caused by the 7 vaccine serotypes in

England and Wales. Subsequently, four years following the switch to Prevenar 13, the additionalreduction in incidence of IPD due to the 7 serotypes in Prevenar ranged from 76% in children less than2 years of age to 91% in children 5-14 years of age. The serotype specific reductions for each of the 5additional serotypes in Prevenar 13 (no cases of serotype 5 IPD were observed) by age group areshown in Table 2 and ranged from 68% (serotype 3) to 100% (serotype 6A) for children less than5 years of age. Significant incidence reductions were also observed in older age groups who had notbeen vaccinated with Prevenar 13 (indirect effect).

Table 2: Serotype specific number of cases and incidence reductions of IPD in 2013/14 compared to2008/09-2009/10 (2008/10) by age in England and Wales<5 years of age 5 to 64 years of age ≥65 years of age2008- 2013/ % Incidence 2008- 2013/ % 2008- 2013/ % Incidence10§ 14§ reduction 10§ 14§ Incidence 10§ 14§ reduction(95% CI*) reduction (95% CI*)(95% CI*)

Additional serotypes covered by Prevenar 131 59 (54) 5 (5) 91% 458 77 83% 102 (89) 13 87%(382) (71) (13)(98%; (88%; (94%;68%)** 74%)** 72%)**3 26 (24) 8 (8) 68% 178 73 59% 256 143 44%(148) (68) (224) (146)(89%; 6%) (72%; (57%;38%)** 27%)**6A 10 (9) 0 (0) 100% 53 (44) 5 (5) 90% 94 (82) 5 (5) 95%(100%; (97%; (99%;62%)** 56%)** 81%)**7F 90 (82) 8 (8) 91% 430 160 63% 173 75 56%(361) (148) (152) (77)(97%; (71%; (70%;74%)** 50%)** 37%)**19A 85 (77) 7 (7) 91% 225 104 54% 279 97 65%(191) (97) (246) (99)(97%; (65%; (75%;75%)** 32%)** 53%)**§ Corrected for proportion of samples serotyped, missing age, denominator compared with 2009/10, andfor the trend in total invasive pneumococcal disease up to 2009/10 (after which no trend correction wasapplied).

* 95% CI inflated from a Poisson interval based on over-dispersion of 2.1 seen from modelling of2000-06 pre-Prevenar all IPD data.

** p<0.005 to cover 6A where p=0.002

Otitis media (OM)

In a published study performed in Israel, using a 2-dose primary series plus booster dose in the secondyear of life, the impact of Prevenar 13 on OM was documented in a population-basedactive-surveillance system with tympanocentesis culturing of middle ear fluid in Israeli children lessthan 2 years of age with OM.

Following the introduction of Prevenar and subsequently Prevenar 13 there was a decline in incidencefrom 2.1 to 0.1 cases per 1000 children (95%) for the Prevenar serotypes plus serotype 6A and adecline in incidence from 0.9 to 0.1 cases per 1000 children (89%) for the additional serotypes 1, 3, 5,7F, and 19A in Prevenar 13. The annual overall pneumococcal incidence of OM declined from 9.6 to2.1 cases per 1000 children (78%) between July 2004 (prior to the introduction of Prevenar) and June2013 (post Prevenar 13 introduction).

In a multicenter observational study in France comparing the periods before and after the switch from

Prevenar to Prevenar 13, there was 16% (2060 to 1725 cases) reduction in all community acquiredpneumonia (CAP) cases in emergency departments in children 1 month to 15 years of age. Reductionswere 53% (167 to 79 cases) (p<0.001) for CAP cases with pleural effusion and 63% (64 to 24 cases)(p<0.001) for microbiologically confirmed pneumococcal CAP cases. In the second year after theintroduction of Prevenar 13 the total number of CAP cases due to the 6 additional vaccine serotypes in

Prevenar 13 was reduced from 27 to 7 isolates (74%).

The decrease in all cause pneumonia cases was most pronounced in the younger vaccinated age groupswith a decrease of 31.8% (757 to 516 cases) and 16.6% (833 to 695 cases) in the age groups <2 yearsand 2 to 5 years, respectively. The incidence in older, predominantly non-vaccinated children (>5years) did not change over the duration of the study.

In an ongoing surveillance system (2004 to 2013) to document the impact of Prevenar andsubsequently Prevenar 13 on CAP in children less than 5 years in Southern Israel using a 2 doseprimary series with a booster dose in the second year of life, there was a reduction of 68% (95% CI 73;61) in outpatient visits and 32% (95% CI 39; 22) in hospitalizations for alveolar CAP following theintroduction of Prevenar 13 when compared to the period before the introduction of Prevenar.

Effect on nasopharyngeal carriage

In a surveillance study in France in children presenting with acute otitis media, changes innasopharyngeal (NP) carriage of pneumococcal serotypes were evaluated following the introduction of

Prevenar (7-valent) and subsequently Prevenar 13. Prevenar 13 significantly reduced NP carriage ofthe 6 additional serotypes (and serotype 6C) combined and individual serotypes 6C, 7F, 19A whencompared with Prevenar. A reduction in carriage was also seen for serotype 3 (2.5% vs 1.1%; p=0.1).

There was no carriage of serotypes 1 and 5 observed.

The effect of pneumococcal conjugate vaccination on nasopharyngeal carriage was studied in arandomised double-blind study in which infants received either Prevenar 13 or Prevenar (7-valent) at2, 4, 6 and 12 months of age in Israel. Prevenar 13 significantly reduced newly identified NPacquisition of the 6 additional serotypes (and serotype 6C) combined and of individual serotypes 1,6A, 6C, 7F, 19A when compared with Prevenar. There was no reduction seen in serotype 3 and forserotype 5 the colonization was too infrequent to assess impact. For 6 of the remaining 7 commonserotypes, similar rates of NP acquisition were observed in both vaccine groups; for serotype 19F asignificant reduction was observed.

In this study, reductions of S. pneumoniae serotypes 19A, 19F, and 6A not susceptible to a number ofantibiotics were documented. The reductions ranged between 34% and 62% depending on serotypeand antibiotic.

Prevenar (7-valent vaccine) protective efficacy in infants and children

The efficacy of 7-valent Prevenar was evaluated in two major studies - the Northern California Kaiser

Permanente (NCKP) study and the Finnish Otitis Media (FinOM) study. Both studies wererandomised, double-blind, active-control studies in which infants were randomised to receive either

Prevenar or control vaccine (NCKP, meningococcal serogroup C CRM-conjugate [MnCC] vaccine;

FinOM, hepatitis B vaccine) in a four-dose series at 2, 4, 6, and 12-15 months of age. The efficacyresults from these studies (for invasive pneumococcal disease, pneumonia, and acute otitis media) arepresented below (Table 3).

Table 3: Summary of efficacy of 7-valent Prevenar1

Test N VE2 95% CI

NCKP: Vaccine-serotype IPD3 30,258 97% 85, 100

NCKP: Clinical pneumonia with abnormal chest X-ray 23,746 35% 4, 56

NCKP: Acute Otitis Media (AOM)4 23,746

Total episodes 7% 4, 10

Recurrent AOM (3 episodes in 6 months, or 4 episodes in 1 year) 9% 3, 15

Recurrent AOM (5 episodes in 6 months, or 6 episodes in 1 year) 23% 7, 36

Tympanostomy tube placement 20% 2, 35

FinOM: AOM 1,662

Total episodes 6% -4, 16

All pneumococcal AOM 34% 21, 45

Vaccine-serotype AOM 57% 44, 671Per protocol2Vaccine efficacy3October 1995 to April 20, 19994October 1995 to April 30, 1998

Prevenar (7-valent) effectiveness

The effectiveness (both direct and indirect effect) of 7-valent Prevenar against pneumococcal diseasehas been evaluated in both three-dose and two-dose primary infant series immunisation programmes,each with booster doses (Table 4). Following the widespread use of Prevenar, the incidence of IPD hasbeen consistently and substantially reduced.

Using the screening method, serotype-specific effectiveness estimates for 2 doses under the age of1 year in the UK were 66 % (-29, 91 %) and 100 % (25, 100 %) for serotype 6B and 23F, respectively.

Table 4: Summary of effectiveness of 7-valent Prevenar for invasive pneumococcal disease

Country Recommended schedule Disease reduction, % 95% CI(year of introduction)

UK (England & Wales)1 (2006) 2, 4, + 13 months Vaccine serotypes: 49, 95%

Two doses under age 1: 85%

USA (2000) 2, 4, 6, + 12-15 months

Children < 52 Vaccine serotypes: 98% 97, 99%

All serotypes: 77% 73, 79%

Persons ≥ 653 Vaccine serotypes: 76% NA

All serotypes: 38% NA

Canada (Quebec)4 2, 4, + 12 months All serotypes: 73% NA(2004) Vaccine serotypes:

2-dose infant series: 99% 92, 100%

Completed schedule:100% 82, 100%1Children < 2 years of age. Calculated vaccine effectiveness as of June 2008 (Broome method).22005 data.32004 data.4Children < 5 years of age. January 2005 to December 2007. Complete effectiveness for routine 2+1 schedule notyet available.

Acute Otitis Media

Effectiveness of Prevenar in a 3+1 schedule has also been observed against acute otitis media andpneumonia since its introduction in a national immunisation programme. In a retrospective evaluationof a large US insurance database, AOM visits were reduced by 42.7 % (95 % CI, 42.4-43.1 %), andprescriptions for AOM by 41.9 % in children younger than 2 years of age, compared with apre-licensure baseline (2004 vs. 1997-99). In a similar analysis, hospitalisations and ambulatory visitsfor all-cause pneumonia were reduced by 52.4 % and 41.1 %, respectively. For those eventsspecifically identified as pneumococcal pneumonia, the observed reductions in hospitalisations andambulatory visits were 57.6 % and 46.9 %, respectively, in children younger than 2 years of age,compared with a pre-licensure baseline (2004 vs. 1997-99). While direct cause-and-effect cannot beinferred from observational analyses of this type, these findings suggest that Prevenar plays animportant role in reducing the burden of mucosal disease (AOM and pneumonia) in the targetpopulation.

Efficacy study in adults 65 years and older

Efficacy against vaccine-type (VT) pneumococcal CAP and IPD was assessed in a large-scalerandomised double-blind, placebo-controlled study (Community-Acquired Pneumonia Immunization

Trial in Adults-CAPiTA) in the Netherlands. 84,496 subjects, 65 years and older received a singlevaccination of either Prevenar 13 or placebo in a 1:1 randomisation.

The CAPiTA study enrolled volunteers ≥ 65 years of age whose demographic and healthcharacteristics may differ from those seeking vaccination.

A first episode of hospitalised, chest X-ray confirmed pneumonia was identified in about 2% of thispopulation (n=1,814 subjects) of which 329 cases were confirmed pneumococcal CAP and 182 caseswere VT pneumococcal CAP in the per protocol and modified intent to treat (mITT) populations.

Efficacy was demonstrated for the primary and secondary endpoints in the per protocol population(Table 5).

Table 5: Vaccine efficacy (VE) for the primary and secondary endpoints of the CAPiTA study (perprotocol population)

Cases

VE (%)

Efficacy endpoint Prevenar 13 Placebo p-value

Total (95.2% CI)group group

Primary endpoint

First episode of confirmed VT 139 49 90 45.56 0.0006pneumococcal CAP (21.82, 62.49)

Secondary endpoints

First episode of confirmed NB/NI1 93 33 60 45.00 0.0067vaccine type pneumococcal CAP (14.21, 65.31)75.00

First episode of VT-IPD2 35 7 28 0.0005(41.06, 90.87)1NB/NI - non-bacteraemic/non-invasive2VT-IPD - vaccine-type invasive pneumococcal disease

The duration of protective efficacy against a first episode of VT pneumococcal CAP,

NB/NI VT pneumococcal CAP, and VT-IPD extended throughout the 4-year study.

The study was not designed to demonstrate efficacy in subgroups, and the number of subjects≥ 85 years of age was not sufficient to demonstrate efficacy in this age group.

A post-hoc analysis was used to estimate the following public health outcomes against clinical CAP(as defined in the CAPiTA study, and based on clinical findings regardless of radiologic infiltrate oretiologic confirmation): vaccine efficacy (VE), incidence rate reduction (IRR), and number needed tovaccinate (NNV) (Table 6).

IRR, also referred to as vaccine preventable disease incidence, is the number of cases of vaccinepreventable disease per 100,000 person-years of observation.

In Table 6, NNV is a measure that quantifies the number of people that need to be vaccinated in orderto prevent one clinical CAP case.

Table 6: Vaccine efficacy (VE) against clinical CAP*

Episodes Vaccine efficacy1 % Incidence per Incidence Number(95% CI) 100,000 person- rate needed to(1-sided p-value) years of observation reduction2 vaccinate3(PYO) (95% CI)

Prevenar Placebo Prevenar Placebo13 13

All 1375 1495 8.1 819.1 891.2 72.2 277episodes (-0.6, 16.1) (-5.3, 149.6)analysis (0.034)

First 1126 1214 7.3 670.7 723.7 53.0 378episode (-0.4, 14.4) (-2.7, 108.7)analysis (0.031)

* Patients with at least 2 of the following: Cough; purulent sputum, temperature >38°C or <36.1°C; pneumonia(auscultatory findings); leukocytosis; C-reactive protein value >3 times the upper limit of normal; hypoxemiawith a partial oxygen pressure <60 mm Hg while breathing room air.1 A Poisson regression model with random effects was used to calculate VE.2 Per 100,000 person-years of observation. IRR is calculated as the incidence in the placebo group minus theincidence in the vaccine group, and was mathematically equivalent to VE × the incidence in the placebo group.3 Based on a 5-year duration of protection. NNV is not a rate but instead indicates the number of cases preventedfor a given number of persons vaccinated. NNV also incorporates the length of the trial or duration of protectionand is calculated as 1 divided by the product of the IRR and duration of protection (or length of trial) (=1/(IRR ×duration).

Immunogenicity studies in adults ≥18 years and the elderly

In adults, an antibody threshold of serotype-specific pneumococcal polysaccharide IgG bindingantibody concentration associated with protection has not been defined. For all pivotal clinical trials, aserotype-specific opsonophagocytosis assay (OPA) was used as a surrogate to assess potential efficacyagainst invasive pneumococcal disease and pneumonia. OPA geometric mean titers (GMTs) measured1-month after each vaccination were calculated. OPA titres are expressed as the reciprocal of thehighest serum dilution that reduces survival of the pneumococci by at least 50 %.

Pivotal trials for Prevenar 13 were designed to show that functional OPA antibody responses for the 13serotypes are non-inferior, and for some serotypes superior, to the 12 serotypes in common with thelicensed 23-valent pneumococcal polysaccharide vaccine [1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F,23F] one month after vaccine administration. The response to serotype 6A, which is unique to

Prevenar 13, was assessed by demonstration of a 4-fold increase in the specific OPA titer abovepre-immunised levels.

Five clinical studies were conducted in Europe and the USA evaluating the immunogenicity of

Prevenar 13 in different age groups ranging from 18-95 years of age. Clinical studies with Prevenar 13currently provide immunogenicity data in adults aged 18 years and older, including adults aged 65 andolder previously vaccinated with one or more doses of 23-valent pneumococcal polysaccharidevaccine, 5 years prior to enrollment. Each study included healthy adults and immuno-competent adultswith stable underlying conditions known to predispose individuals to pneumococcal infection (i.e.,chronic cardiovascular disease, chronic pulmonary disease including asthma, renal disorders anddiabetes mellitus, chronic liver disease including alcoholic liver disease), and adults with risk factorssuch as smoking and alcohol abuse.

Immunogenicity and safety of Prevenar 13 has been demonstrated in adults aged 18 years and olderincluding those previously vaccinated with a pneumococcal polysaccharide vaccine.

Adults not previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

In a head-to-head, comparative trial conducted in adults aged 60-64 years, subjects received a singledose of either Prevenar 13 or 23-valent pneumococcal polysaccharide vaccine. In the same studyanother group of adults aged 50-59 years and another group of adults aged 18-49 years received asingle dose of Prevenar 13.

Table 7 compares the OPA GMTs, 1-month post-dose, in 60-64 year olds given either a single dose of

Prevenar 13 or 23-valent pneumococcal polysaccharide vaccine, and in 50-59 year olds given a singledose of Prevenar 13.

Table 7: OPA GMTs in adults aged 60-64 years given Prevenar 13 or 23-valent pneumococcalpolysaccharide vaccine (PPSV23) and in adults aged 50-59 years given Prevenar 13a,b,c

Prevenar 13 Prevenar 13 PPSV23 Prevenar 13 Prevenar 13 Relative50-59 Years 60-64 Years 60-64 Years 50-59 Relative to to PPSV23,

N=350-384 N=359-404 N=367-402 60-64 Years 60-64 Years

Serotype GMT GMT GMT GMR (95% CI) GMR (95% CI)1 200 146 104 1.4 (1.08, 1.73) 1.4 (1.10, 1.78)3 91 93 85 1.0 (0.81, 1.19) 1.1 (0.90, 1.32)4 2833 2062 1295 1.4 (1.07, 1.77) 1.6 (1.19, 2.13)5 269 199 162 1.4 (1.01, 1.80) 1.2 (0.93, 1.62)6A† 4328 2593 213 1.7 (1.30, 2.15) 12.1 (8.63, 17.08)6B 3212 1984 788 1.6 (1.24, 2.12) 2.5 (1.82, 3.48)7F 1520 1120 405 1.4 (1.03, 1.79) 2.8 (1.98, 3.87)9V 1726 1164 407 1.5 (1.11, 1.98) 2.9 (2.00, 4.08)14 957 612 692 1.6 (1.16, 2.12) 0.9 (0.64, 1.21)18C 1939 1726 925 1.1 (0.86, 1.47) 1.9 (1.39, 2.51)19A 956 682 352 1.4 (1.16, 1.69) 1.9 (1.56, 2.41)19F 599 517 539 1.2 (0.87, 1.54) 1.0 (0.72, 1.28)23F 494 375 72 1.3 (0.94, 1.84) 5.2 (3.67, 7.33)a Non-inferiority was defined as the lower limit of the 2-sided 95% CI for GMR was greater than 0.5.b Statistically significantly greater response was defined as the lower bound of the 2-sided 95% CI for the GMRwas greater than 1.c For serotype 6A†, which is unique to Prevenar 13, a statistically significantly greater response was defined asthe lower bound of the 2-sided 95% CI for the GMR being greater than 2.

In adults aged 60-64 years, OPA GMTs to Prevenar 13 were non-inferior to the OPA GMTs elicited tothe 23-valent pneumococcal polysaccharide vaccine for the twelve serotypes common to bothvaccines. For 9 serotypes, the OPA titers were shown to be statistically significantly greater in

Prevenar 13 recipients.

In adults aged 50-59 years, OPA GMTs to all 13 serotypes in Prevenar 13 were non-inferior to the

Prevenar 13 responses in adults aged 60-64 years. For 9 serotypes, immune responses were related toage, with adults in the 50-59 years group showing statistically significantly greater responses thanadults aged 60-64 years.

In all adults ≥ 50 years who received a single dose of Prevenar 13, the OPA titers to serotype 6A weresignificantly greater than in adults ≥ 60 years who received a single dose of 23-valent pneumococcalpolysaccharide vaccine.

One year after vaccination with Prevenar 13 OPA titers had declined compared to one month aftervaccination, however, OPA titers for all serotypes remained higher than levels at baseline:

OPA GMT levels at baseline OPA GMT levels one year after

Prevenar 13

Adults 50-59 years not previouslyvaccinated with 23-valent 5 to 45 20 to 1234pneumococcal polysaccharide vaccine

Adults 60-64 years not previouslyvaccinated with 23-valent 5 to 37 19 to 733pneumococcal polysaccharide vaccine

Table 8 shows OPA GMTs 1-month after a single dose of Prevenar 13 in 18-49 year olds compared to60-64 year olds.

Table 8: OPA GMTs in adults aged 18-49 years and 60-64 years given Prevenar 13a,b18-49 Years18-49 Years 60-64 Years Relative to

N=836-866 N=359-404 60-64 Years

Serotype GMTb GMTb GMR (95% CIc)1 353 146 2.4 (2.03, 2.87)3 91 93 1.0 (0.84, 1.13)4 4747 2062 2.3 (1.92, 2.76)5 386 199 1.9 (1.55, 2.42)6A 5746 2593 2.2 (1.84, 2.67)6B 9813 1984 4.9 (4.13, 5.93)7F 3249 1120 2.9 (2.41, 3.49)9V 3339 1164 2.9 (2.34, 3.52)14 2983 612 4.9 (4.01, 5.93)18C 3989 1726 2.3 (1.91, 2.79)19A 1580 682 2.3 (2.02, 2.66)19F 1533 517 3.0 (2.44, 3.60)23F 1570 375 4.2 (3.31, 5.31)a Non-inferiority was defined as the lower limit of the 2-sided 95% CI for GMR was greater than 0.5.b Statistically significantly greater response was defined as the lower bound of the 2-sided 95% CI for the GMRwas greater than 1.c Confidence intervals (CIs) for the ratio are back transformations of a confidence interval based on the Student tdistribution for the mean difference of the logarithms of the measures.

In adults aged 18-49 years, OPA GMTs to all 13 serotypes in Prevenar 13 were non-inferior to the

Prevenar 13 responses in adults aged 60-64 years.

One year after vaccination with Prevenar 13 OPA titers had declined compared to one month aftervaccination, however OPA titers for all serotypes remained higher than levels at baseline.

OPA GMT levels at baseline OPA GMT levels one year after

Prevenar 13

Adults 18-49 years not previouslyvaccinated with 23-valent 5 to 186 23 to 2948pneumococcal polysaccharide vaccine

Adults previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

Immune responses to Prevenar 13 and 23-valent pneumococcal polysaccharide vaccine were comparedin a head to head trial in adults aged ≥ 70 years, who had received a single dose of pneumococcalpolysaccharide vaccine at least 5 years before study vaccination.

Table 9 compares the OPA GMTs, 1-month post-dose, in pneumococcal polysaccharide vaccinatedadults aged ≥ 70 years given a single dose of either Prevenar 13 or 23-valent pneumococcalpolysaccharide vaccine.

Table 9: OPA GMTs in pneumococcal polysaccharide vaccinated adults aged≥ 70 years given either Prevenar 13 or 23-valent pneumococcal polysaccharide vaccine (PPSV23)a,b,c

Prevenar 13 PPSV23 Prevenar OPA GMT

N=400-426 N=395-445 Relative to PPSV23

Serotype OPA GMT OPA GMT GMR (95% CI)1 81 55 1.5 (1.17, 1.88)3 55 49 1.1 (0.91, 1.35)4 545 203 2.7 (1.93, 3.74)5 72 36 2.0 (1.55, 2.63)6A† 903 94 9.6 (7.00, 13.26)6B 1261 417 3.0 (2.21, 4.13)7F 245 160 1.5 (1.07, 2.18)9V 181 90 2.0 (1.36, 2.97)14 280 285 1.0 (0.73, 1.33)18C 907 481 1.9 (1.42, 2.50)19A 354 200 1.8 (1.43, 2.20)19F 333 214 1.6 (1.17, 2.06)23F 158 43 3.7 (2.69, 5.09)a Non-inferiority was defined as the lower limit of the 2-sided 95% CI for GMR was greater than 0.5.b Statistically significantly greater response was defined as the lower bound of the 2-sided 95% CI for the GMRwas greater than 1.c For serotype 6A†, which is unique to Prevenar 13, a statistically significantly greater response was defined asthe lower bound of the 2-sided 95% CI for the GMR greater than 2.

In adults vaccinated with pneumococcal polysaccharide vaccine at least 5 years prior to the clinicalstudy, OPA GMTs to Prevenar 13 were non-inferior to the 23-valent pneumococcal polysaccharidevaccine responses for the 12 serotypes in common. Furthermore, in this study statistically significantlygreater OPA GMTs were demonstrated for 10 of the 12 serotypes in common. Immune responses toserotype 6A were statistically significantly greater following vaccination with Prevenar 13 than after23-valent pneumococcal polysaccharide vaccine.

One year after vaccination with Prevenar 13 in adults aged 70 years and over who were vaccinatedwith 23-valent pneumococcal polysaccharide vaccine, at least 5 years prior to study entry, OPA titershad declined compared to one month after vaccination, however, OPA titers for all serotypes remainedhigher than levels at baseline:

OPA GMT levels at baseline OPA GMT levels one year after

Prevenar 13

Adults ≥ 70 years vaccinated with23-valent pneumococcal 9 to 122 18 to 381polysaccharide vaccine at least 5years prior

Immune responses in Special Populations

Individuals with the conditions described below have an increased risk of pneumococcal disease. Theclinical relevance of the antibody levels elicited by Prevenar 13 in these special populations isunknown.

Sickle cell disease

An open label single arm study in France, Italy, UK, US, Lebanon, Egypt and Saudi Arabia with2 doses of Prevenar 13 given 6 months apart was conducted in 158 children and adolescents ≥ 6 to< 18 years of age with sickle cell disease who were previously vaccinated with one or more doses of23-valent pneumococcal polysaccharide vaccine at least 6 months prior to enrollment. After the firstvaccination, Prevenar 13 elicited antibody levels measured by both IgG GMCs and OPA GMTs thatwere statistically significantly higher when compared to levels prior to vaccination. After the seconddose immune responses were comparable to those after the first dose. One year after the second dose,antibody levels measured by both IgG GMCs and OPA GMTs were higher than levels prior to the firstdose of Prevenar 13, except for the IgG GMCs for serotypes 3 and 5 that were numerically similar.

Additional Prevenar (7-valent) immunogenicity data: children with sickle cell disease

The immunogenicity of Prevenar has been investigated in an open-label, multicentre study in49 infants with sickle cell disease. Children were vaccinated with Prevenar (3 doses one month apartfrom the age of 2 months), 46 of these children also received a 23-valent pneumococcalpolysaccharide vaccine at the age of 15-18 months. After primary immunisation, 95.6 % of thesubjects had antibody levels of at least 0.35 μg/ml for all seven serotypes found in Prevenar.

A significant increase was seen in the concentrations of antibodies against the seven serotypes after thepolysaccharide vaccination, suggesting that immunological memory was well established.

HIV infection

Children and adults not previously vaccinated with a pneumococcal vaccine

HIV-infected children and adults with CD4 ≥ 200 cells/µL (mean 717.0 cells/μL), viral load< 50,000 copies/ml (mean 2090.0 copies/ml), free of active AIDS-related illness and not previouslyvaccinated with a pneumococcal vaccine received 3 doses of Prevenar 13. As per generalrecommendations, a single dose of 23-valent pneumococcal polysaccharide vaccine was subsequentlyadministered. Vaccines were administered at 1 month intervals. Immune responses were assessed in259-270 evaluable subjects approximately 1 month after each dose of vaccine. After the first dose,

Prevenar 13 elicited antibody levels, measured by both IgG GMCs and OPA GMTs that werestatistically significantly higher when compared to levels prior to vaccination. After the second andthird dose of Prevenar 13, immune responses were similar or higher than those after the first dose.

Adults previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

HIV-infected adults ≥ 18 years of age with CD4 ≥ 200 cells/µL (mean 609.1 cells/µL) and viral load< 50,000 copies/ml (mean 330.6 copies/ml), who were free of active AIDS-related illness and werepreviously vaccinated with 23-valent pneumococcal polysaccharide vaccine administered at least6 months prior to enrollment, received 3 doses of Prevenar 13, at enrollment, 6 months, and 12 monthsafter the first dose of Prevenar 13. Immune responses were assessed in 231-255 evaluable subjectsapproximately 1 month after each dose of Prevenar 13. After the first dose, Prevenar 13 elicitedantibody levels measured by both IgG GMCs and OPA GMTs that were statistically significantlyhigher when compared to levels prior to vaccination. After the second and third dose of Prevenar 13,immune responses were comparable or higher than those after the first dose. In the study 162 subjectshad received one prior dose of 23-valent pneumococcal polysaccharide vaccine, 143 subjects 2 priordoses and 26 subjects more than 2 prior doses of 23-valent polysaccharide vaccine. Subjects whoreceived two or more previous doses of 23-valent pneumococcal polysaccharide vaccine showed asimilar immune response compared with subjects who received a single previous dose.

Haematopoietic stem cell transplant

Children and adults with an allogeneic haematopoietic stem cell transplant (HSCT) at ≥ 2 years of agewith complete haematologic remission of underlying disease or with very good partial remission in thecase of lymphoma and myeloma received three doses of Prevenar 13 with an interval of at least1 month between doses. The first dose was administered at 3 to 6 months after HSCT. A fourth(booster) dose of Prevenar 13 was administered 6 months after the third dose. As per generalrecommendations, a single dose of 23-valent pneumococcal polysaccharide vaccine was administered1 month after the fourth dose of Prevenar 13. Immune responses as measured by IgG GMCs wereassessed in 168-211 evaluable subjects approximately 1 month after vaccination. Prevenar 13 elicitedincreased antibody levels after each dose of Prevenar 13. Immune responses after the fourth dose of

Prevenar 13 were significantly increased for all serotypes compared with after the third dose.

Functional antibody titers (OPA titers) were not measured in this study.

Not applicable.

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, single and repeated dose toxicity, local tolerance, and reproduction and developmentaltoxicity.

Sodium chloride

Succinic acid

Polysorbate 80

Water for injections

For adjuvant, see section 2.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Store in a refrigerator (2°C - 8°C). Do not freeze.

Prevenar 13 is stable at temperatures up to 25°C for four days. At the end of this period Prevenar 13should be used or discarded. These data are intended to guide health care professionals in case oftemporary temperature excursions.

0.5 ml suspension for injection in pre-filled syringe (Type I glass) with a plunger stopper (latex-freechlorobutyl rubber) and protective-tip cap (latex-free isoprene bromobutyl rubber).

Pack sizes of 1, 10 and 50, with or without needle.

Not all pack sizes may be marketed.

During storage, a white deposit and clear supernatant can be observed. This does not constitute a signof deterioration.

The vaccine should be shaken well to obtain a homogeneous white suspension prior to expelling airfrom the syringe, and should be inspected visually for any particulate matter and/or variation ofphysical aspect prior to administration. Do not use if the content appears otherwise.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/09/590/001

EU/1/09/590/002

EU/1/09/590/003

EU/1/09/590/004

EU/1/09/590/005

EU/1/09/590/006

Date of first authorisation: 09 December 2009

Date of latest renewal: 18 September 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.