Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: vaccines, pneumococcal vaccines, ATC code: J07AL52 
Epidemiological data

The 10 pneumococcal serotypes included in this vaccine represent the major disease-causing serotypes in Europe covering approximately 56% to 90% of invasive pneumococcal disease (IPD) in children <5 years of age. In this age group, serotypes 1, 5 and 7F account for 3.3% to 24.1% of IPD depending on the country and time period studied.

Pneumonia of different aetiologies is a leading cause of childhood morbidity and mortality globally. In prospective studies, Streptococcus pneumoniae was estimated to be responsible for 30-50% of pneumonia cases.

Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can be responsible for 60-70% of clinical episodes of AOM. Streptococcus pneumoniae and Non-Typeable Haemophilus influenzae (NTHi) are the most common causes of bacterial AOM worldwide.
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Efficacy and effectiveness in clinical trials

In a large-scale phase III/IV, double-blind, cluster-randomized, controlled, clinical trial in Finland (FinIP), children were randomised into 4 groups according to the two infant vaccination schedules [2-dose (3, 5 months of age) or 3-dose (3, 4, 5 months of age) primary schedule followed by a booster dose as of 11 months of age] to receive either Synflorix (2/3rd of clusters) or hepatitis vaccines as control (1/3rd of clusters). In the catch-up cohorts, children between 7–11 months of age at first vaccine dose received Synflorix or hepatitis B control vaccine according to a 2-dose primary schedule followed by a booster dose and children between 12–18 months of age at first vaccine dose received 2 doses of either Synflorix or hepatitis A control vaccine. Average follow-up, from first vaccination,
was 24 to 28 months for invasive disease and hospital-diagnosed pneumonia. In a nested study, infants were followed up till approximately 21 months of age to assess impact on nasopharyngeal carriage and physician-diagnosed AOM reported by parents.

In a large-scale phase III, randomized, double-blind clinical trial (Clinical Otitis Media and Pneumonia Study - COMPAS) conducted in Argentina, Panama and Colombia, healthy infants aged 6 to 16 weeks received either Synflorix or hepatitis B control vaccine at 2, 4 and 6 months of age followed respectively by either Synflorix or hepatitis A control vaccine at 15 to 18 months of age.

Invasive pneumococcal disease (which includes sepsis, meningitis, bacteraemic pneumonia and bacteraemia)

Effectiveness/efficacy in infant cohort below 7 months of age at enrolment 
Vaccine effectiveness or efficacy (VE) was demonstrated in preventing culture-confirmed IPD due to vaccine pneumococcal serotypes when Synflorix was given to infants in either 2+1 or 3+1 schedules in FinIP or 3+1 schedule in COMPAS (see Table 1).

Table 1: Number of vaccine serotype IPD cases and vaccine effectiveness (FinIP) or efficacy (COMPAS) in infants below 7 months of age at enrolment receiving at least one vaccine dose (Infant total vaccinated cohort)
FinIP                                        COMPAS
VE                                       VE
No. of IPD cases                                     No. of IPD cases (95% CI)                                 (95% CI)
Type of Synflorix Synflorix                                             Synflorix Control(2)
IPD        3+1          2+1                                            3+1       Control 3+1        2+1                                 3+1 schedule schedule                                            schedule schedule    schedule                           schedule
N            N           N                                  N           N 10,273        10,054     10,200                              11,798     11,799 Vaccine
100%(3)    91.8%(4)                            100%(5) serotype       0            1          12                                   0          18 (82.8; 100) (58.3; 99.6)                        (77.3; 100)
IPD(1)
Serotype                                           100%       100%
0            0           5                                   0          2            - 6B IPD                                         (54.9; 100) (54.5; 100) Serotype                                           100%       100%                                100% 0            0           4                                   0          9 14 IPD                                        (39.6; 100) (43.3; 100)                         (49.5; 100) IPD Invasive Pneumococcal Disease
VE Vaccine effectiveness (FinIP) or efficacy (COMPAS)
N      number of subjects per group
CI     Confidence Interval
(1) In FinIP apart from serotypes 6B and 14, culture-confirmed vaccine serotype IPD cases included 7F (1 case in the Synflorix 2+1 clusters), 18C, 19F and 23F (1 case of each in the control clusters). In COMPAS, serotypes 5 (2 cases), 18C (4 cases) and 23F (1 case) were detected in control group in addition to serotypes 6B and 14.
(2) the 2 groups of control clusters of infants were pooled
(3) p-value<0.0001
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(4)    p-value=0.0009
(5)    in the ATP cohort VE was 100% (95% CI: 74.3; 100; 0 versus 16 cases) 
In FinIP the overall observed VE against culture-confirmed IPD was 100% (95% CI: 85.6; 100; 0 versus 14 cases) for the 3+1 schedule, 85.8% (95% CI: 49.1; 97.8; 2 versus 14 cases) for the 2+1 schedule and 93.0% (95% CI: 74.9; 98.9; 2 versus 14 cases) regardless of the primary vaccination schedule. In COMPAS it was 66.7% (95% CI: 21.8; 85.9; 7 versus 21 cases).

Effectiveness following catch-up immunisation

Among the 15,447 children in the catch-up vaccinated cohorts, there were no culture-confirmed IPD cases in the Synflorix groups while 5 vaccine serotype IPD cases were observed in the control groups (serotypes 4, 6B, 7F, 14 and 19F).

Pneumonia

Efficacy against pneumonia was assessed in COMPAS. The mean duration follow-up from 2 weeks post-dose 3 in the ATP cohort was 23 months (range from 0 to 34 months) for the interim analysis (IA) and 30 months (range from 0 to 44 months) for the end-of-study analysis. At the end of this IA or end-of-study ATP follow-up period, the mean age was 29 months (range from 4 to 41 months) and 36 months (range from 4 to 50 months), respectively. The proportion of subjects who received the booster dose in the ATP cohort was 92.3% in both analyses.

Efficacy of Synflorix against first episodes of likely bacterial Community Acquired Pneumonia (CAP) occurring from 2 weeks after the administration of the 3rd dose was demonstrated in the ATP cohort (P value ≤ 0.002) in the interim analysis (event-driven; primary objective).
Likely bacterial CAP (B–CAP) is defined as radiologically confirmed CAP cases with either alveolar consolidation/pleural effusion on the chest X-ray, or with non-alveolar infiltrates but with C reactive protein (CRP) ≥ 40 mg/l.

The vaccine efficacy against B–CAP observed at the interim analysis is presented below (table 2).

Table 2: Numbers and percentages of subjects with first episodes of B–CAP occurring from 2 weeks after the administration of the 3rd dose of Synflorix or control vaccine and vaccine efficacy (ATP cohort)
Synflorix                      Control vaccine
N=10,295                           N=10,201                   Vaccine efficacy n             % (n/N)             n            % (n/N)

240                 2.3%            304                  3.0%             22.0%
(95% CI: 7.7; 34.2)
N   number of subjects per group n/% number/percentage of subjects reporting a first episode of B–CAP anytime from 2 weeks after the administration of the 3rd dose
CI  Confidence Interval

In the interim analysis (ATP cohort), the vaccine efficacy against first episodes of CAP with alveolar consolidation or pleural effusion (C–CAP, WHO definition) was 25.7% (95% CI: 8.4; 39.6) and against first episodes of clinically suspected CAP referred for X-ray was 6.7% (95% CI: 0.7; 12.3).

At the end-of-study analysis (ATP cohort), the vaccine efficacy (first episodes) against B–CAP was 18.2% (95% CI: 4.1; 30.3), against C–CAP 22.4% (95% CI: 5.7; 36.1) and against clinically suspected CAP referred for X-ray 7.3% (95% CI: 1.6; 12.6). Efficacy was 100% (95% CI: 41.9; 100) against bacteraemic pneumococcal pneumonia or empyema due to vaccine serotypes. The protection against B–CAP before booster dose and at the time or after booster dose was 13.6% (95% CI: -11.3; 33.0) and 21.7% (95% CI: 3.4; 36.5) respectively. For C–CAP it was 15.1% (95% CI: -15.5; 37.6) and 26.3%
(95% CI: 4.4; 43.2) respectively.

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The reduction in B–CAP and C–CAP was greatest in children < 36 months of age (vaccine efficacy of 20.6% (95% CI: 6.5; 32.6) and 24.2% (95% CI: 7.4; 38.0) respectively). Vaccine efficacy results in children > 36 months of age suggest a waning of protection. The persistence of protection against B–CAP and C–CAP beyond the age of 36 months is currently not established.

The results of the COMPAS study, which was performed in Latin America, should be interpreted with caution due to possible differences in epidemiology of pneumonia in different geographical locations.

In the FinIP study, vaccine effectiveness in reducing hospital-diagnosed pneumonia cases (identified based on the ICD 10 codes for pneumonia) was 26.7% (95% CI: 4.9; 43.5) in the 3+1 infant schedule and 29.3% (95% CI: 7.5; 46.3) in the 2+1 infant schedule. For catch-up vaccination, vaccine effectiveness was 33.2% (95% CI: 3.0; 53.4) in the 7–11 month cohort and 22.4% (95% CI: -8.7; 44.8) in the 12–18 month cohort.

Acute Otitis Media (AOM)

Two efficacy studies, COMPAS and POET (Pneumococcal Otitis Media Efficacy Trial), were conducted with pneumococcal conjugate vaccines containing protein D: Synflorix and an investigational 11-valent conjugate vaccine (which in addition contained serotype 3), respectively.

In COMPAS, 7,214 subjects [Total Vaccinated cohort (TVC)] were included in the AOM efficacy analysis of which 5,989 subjects were in the ATP cohort (Table 3).

Table 3: Vaccine efficacy against AOM(1) in COMPAS
Vaccine efficacy
Type or cause of AOM                            (95% CI)
ATP(2)
16.1%
Clinical AOM
(-1.1; 30.4)(3)
56.1%
Any pneumococcal serotype
(13.4; 77.8)
67.1%
10 pneumococcal vaccine serotypes
(17.0; 86.9)
15.0%(4)
Non-typeable Haemophilus influenzae (NTHi)
(-83.8; 60.7)
CI     Confidence Interval
(1)    First episode
(2)    Follow up period for a maximum of 40 months from 2 weeks after third primary dose (3)    Not statistically significant by pre-defined criteria (One sided p=0.032). However, in TVC cohort, vaccine efficacy against first clinical AOM episode was 19% (95% CI: 4.4; 31.4).
(4)    Not statistically significant.

In another large randomised double-blind trial (POET) conducted in the Czech Republic and in Slovakia, 4,907 infants (ATP cohort) received either the 11-valent investigational vaccine (11Pn-PD) containing the 10 serotypes of Synflorix (along with serotype 3 for which efficacy was not demonstrated) or a control vaccine (hepatitis A vaccine) according to a 3, 4, 5 and 12-15 months vaccination schedule.

Efficacy of the 11 Pn-PD vaccine against the first occurrence of vaccine serotype AOM episode was 52.6% (95% CI: 35.0; 65.5). Serotype specific efficacy against the first AOM episode was demonstrated for serotypes 6B (86.5%, 95% CI: 54.9; 96.0), 14 (94.8%, 95% CI: 61.0; 99.3), 19F (43.3%, 95% CI: 6.3; 65.4) and 23F (70.8%, 95% CI: 20.8; 89.2). For other vaccine serotypes, the number of AOM cases was too limited to allow any efficacy conclusion to be drawn. Efficacy against any AOM episode due to any pneumococcal serotype was 51.5% (95% CI: 36.8; 62.9). The vaccine efficacy against the first episode of NTHi AOM was 31.1% (95% CI: -3.7; 54.2, not significant).
Efficacy against any NTHi AOM episode was 35.3% (95% CI: 1.8; 57.4). The estimated vaccine 
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efficacy against any clinical episodes of otitis media regardless of aetiology was 33.6% (95% CI: 20.8; 44.3).

Based on immunological bridging of the functional vaccine response (OPA) of Synflorix with the 11-valent formulation used within POET, it is expected that Synflorix provides similar protective efficacy against pneumococcal AOM.

No increase in the incidence of AOM due to other bacterial pathogens or non-vaccine/non-vaccine related serotypes was observed in either COMPAS (based on the few cases reported) or POET trial.

Effectiveness against physician-diagnosed AOM reported by parents was studied in the nested study within the FinIP trial. Vaccine effectiveness was 6.1% (95% CI: -2.7; 14.1) for the 3+1 schedule and 7.4% (95% CI -2.8; 16.6) for 2+1 schedule for this AOM endpoint in the infant vaccinated cohort.

Impact on nasopharyngeal carriage (NPC)

The effect of Synflorix on nasopharyngeal carriage was studied in 2 double-blind randomised studies using an inactive control: in the nested study of FinIP in Finland (5,023 subjects) and in COMPAS (1,700 subjects).

In both COMPAS and the nested Finnish study, Synflorix reduced vaccine type carriage with an apparent increase in non-vaccine (excluding vaccine-related) serotypes observed after booster. The results were not statistically significant across all analyses in COMPAS. However, taken together there was a trend for decrease in overall pneumococcal carriage.

In both studies there were significant decrease of individual serotypes 6B and 19F. In the nested Finnish study, a significant reduction was also observed for individual serotypes 14, 23F and, in the 3 dose primary schedule, for the cross-reactive serotype 19A.

In a clinical study NPC was assessed in HIV positive infants (N = 83) and HIV negative infants born from HIV positive mothers (N = 101) and compared to HIV negative infants born from HIV negative mothers (N = 100). The HIV exposure or infection did not appear to alter the effect of Synflorix on pneumococcal carriage up to 24–27 months of age, i.e. up to 15 months following booster vaccination.

Effectiveness in post-marketing surveillance

In Brazil, Synflorix was introduced into the national immunisation programme (NIP) using a 3+1 schedule in infants (2, 4, 6 months of age and a booster dose at 12 months) with a catch-up campaign in children up to 2 years of age. Based on almost 3 years of surveillance following Synflorix introduction, a matched case-control study reported a significant decrease in culture or PCR confirmed IPD due to any vaccine serotype, and IPD due to individual serotypes 6B, 14 and 19A.

Table 4: Summary of effectiveness of Synflorix for IPD in Brazil
Types of IPD(1)                       Adjusted Effectiveness(2)
% (95% CI)
(3)
Any vaccine serotype IPD                                83.8% (65.9; 92.3) 
-   Invasive pneumonia or bacteraemia                      81.3% (46.9; 93.4) 
-   Meningitis                                             87.7% (61.4; 96.1) 


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IPD due to individual serotypes(4)

-   6B                                                       82.8% (23.8; 96.1) 
-   14                                                       87.7% (60.8; 96.1) 
-   19A                                                      82.2% (10.7; 96.4) 
(1) Culture or PCR confirmed IPD
(2) The adjusted effectiveness represents the percent reduction in IPD in the Synflorix vaccinated group compared to the unvaccinated group, controlling for confounding factors.
(3) Culture or PCR confirmed cases for serotypes 4, 6B, 7F, 9V, 14, 18C, 19F and 23F contributed to the analysis.
(4) Individual serotypes for which statistical significance was reached in the effectiveness analysis controlling for confounding factors (no adjustment for multiplicity performed).

In Finland, Synflorix was introduced into NIP with a 2+1 schedule in infants (3, 5 months of age and a booster dose at 12 months) without catch-up campaign. Before and after NIP comparison suggests a significant decrease in the incidence of any culture confirmed IPD, any vaccine serotype IPD and IPD due to serotype 19A.

Table 5: Rates of IPD and the corresponding rate reductions in Finland IPD                Incidence per 100,000 person years                   Relative rate reduction(1) % (95% CI)
Before NIP              After NIP
Any culture confirmed                   62.9                       12.9                  80% (72; 85) 
Any vaccine serotype(2)                 49.1                        4.2                  92% (86; 95) Serotype 19A                              5.5                  2.1                   62% (20; 85) (1) The relative rate reduction indicates how much the incidence of IPD in children of ≤5 years of age was reduced in the Synflorix cohort (followed for 3 years after NIP introduction) versus age and season matched non-vaccinated historical cohorts (each followed for 3 year periods before introduction of Synflorix into NIP).
(2) Culture confirmed cases for serotypes 1, 4, 6B, 7F, 9V, 14, 18C, 19F and 23F contributed to the analysis.

In Quebec, Canada, Synflorix was introduced into the infant immunisation programme (2 primary doses to infants less than 6 months of age and a booster dose at 12 months) following 4.5 years of use of 7-valent Prevenar. Based on 1.5 years of surveillance following Synflorix introduction, with over 90% coverage in the vaccine-eligible age group, a decrease in vaccine serotype IPD incidence (largely due to changes in serotype 7F disease) was observed with no concomitant increase in non-vaccine serotype IPD incidence. Overall, the incidence of IPD was 35/100,000 person-years in those cohorts exposed to Synflorix, and 64/100,000 person-years in those exposed to 7-valent Prevenar, representing a statistically significant difference (p = 0.03). No direct cause-and-effect can be inferred from observational studies of this type.

Immunogenicity data

Immunologic non-inferiority to 7-valent Prevenar
The assessment of potential efficacy against IPD pre-licensure was based on a comparison of immune responses to the seven serotypes shared between Synflorix and another pneumococcal conjugate vaccine for which protective efficacy was evaluated previously (i.e. 7-valent Prevenar), as recommended by the WHO. Immune responses to the extra three serotypes in Synflorix were also measured.


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In a head-to-head comparative trial with 7-valent Prevenar, non-inferiority of the immune response to Synflorix measured by ELISA was demonstrated for all serotypes, except for 6B and 23F (upper limit of the 96.5% CI around the difference between groups >10%) (Table 6). For serotypes 6B and 23F, respectively, 65.9% and 81.4% of infants vaccinated at 2, 3 and 4 months reached the antibody threshold (i.e. 0.20 µg/ml) one month after the third dose of Synflorix versus 79.0% and 94.1% respectively, after three doses of 7-valent Prevenar. The clinical relevance of these differences is unclear, as Synflorix was observed to be effective against IPD caused by serotype 6B in a double- blind, cluster-randomized clinical study (see Table 1).

The percentage of vaccinees reaching the threshold for the three additional serotypes in Synflorix (1, 5 and 7F) was respectively 97.3%, 99.0% and 99.5% and was at least as good as the aggregate 7-valent Prevenar response against the 7 common serotypes (95.8%).

Table 6: Comparative analysis between 7-valent Prevenar and Synflorix in percentage of subjects with antibody concentrations > 0.20 µg/ml one month post-dose 3 Difference in %  0.20g/ml (7-
Synflorix        7-valent Prevenar
Antibody                                                      valent Prevenar minus Synflorix) N          %         N           %             %               96.5% CI Anti-4            1106       97.1      373         100           2.89         1.71       4.16 Anti-6B           1100       65.9      372         79.0         13.12         7.53      18.28 Anti-9V           1103       98.1      374         99.5          1.37         -0.28      2.56 Anti-14           1100       99.5      374         99.5         -0.08         -1.66      0.71 Anti-18C          1102       96.0      374         98.9          2.92         0.88       4.57 Anti-19F          1104       95.4      375         99.2          3.83         1.87       5.50 Anti-23F          1102       81.4      374         94.1         12.72         8.89      16.13 
Post-primary antibody geometric mean concentrations (GMCs) elicited by Synflorix against the seven serotypes in common were lower than those elicited by 7-valent Prevenar. Pre-booster GMCs (8 to 12 months after the last primary dose) were generally similar for the two vaccines. After the booster dose the GMCs elicited by Synflorix were lower for most serotypes in common with 7-valent Prevenar.

In the same study, Synflorix was shown to elicit functional antibodies to all vaccine serotypes. For each of the seven serotypes in common, 87.7% to 100% of Synflorix vaccinees and 92.1% to 100% of 7-valent Prevenar vaccinees reached an OPA titre  8 one month after the third dose. The difference between both vaccines in terms of percentage of subjects with OPA titres  8 was <5% for all serotypes in common, including 6B and 23F. Post-primary and post-booster OPA antibody geometric mean titres (GMTs) elicited by Synflorix were lower than those elicited by 7-valent Prevenar for the seven shared serotypes, except for serotype 19F.

For serotypes 1, 5 and 7F, the percentages of Synflorix vaccinees reaching an OPA titre  8 were respectively 65.7%, 90.9% and 99.6% after the primary vaccination course and 91.0%, 96.3% and 100% after the booster dose. The OPA response for serotypes 1 and 5 was lower in magnitude than the response for each of the other serotypes. The implications of these findings for protective efficacy are not known. The response to serotype 7F was in the same range as for the seven serotypes in common between the two vaccines.

It has also been demonstrated that Synflorix induces an immune response to the cross-reactive serotype 19A with 48.8% (95% CI: 42.9; 54.7) of vaccinees reaching an OPA titre  8 one month after a booster dose.

The administration of a fourth dose (booster dose) in the second year of life elicited an anamnestic antibody response as measured by ELISA and OPA for the vaccine serotypes and the cross-reactive serotype 19A demonstrating the induction of immune memory after the three-dose primary course.

Additional immunogenicity data

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Infants from 6 weeks to 6 months of age:
3-dose primary schedule

In clinical studies the immunogenicity of Synflorix was evaluated after a 3-dose primary vaccination series (6941 subjects) according to different schedules (including 6-10-14 weeks, 2-3-4, 3-4-5 or 2-4-6 months of age) and after a fourth (booster) dose (5645 subjects) given at least 6 months after the last primary dose and from the age of 9 months onwards. In general, comparable vaccine responses were observed for the different schedules, although somewhat higher immune responses were noted for the 2-4-6 month schedule.


A clinical study evaluated the immunogenicity of Synflorix in 2-dose or 3-dose primed subjects in four European countries. Although there was no significant difference between the two groups in the percentages of subjects with antibody concentration  0.20 g/mL (ELISA), the percentages of subjects for serotypes 6B and 23F were lower than for the other vaccine serotypes (Table 7 and Table 8). The percentage of subjects with OPA titres  8 in 2-dose primed subjects compared to 3-dose primed subjects were lower for serotypes 6B, 18C and 23F (74.4%, 82.8%, 86.3% respectively for the 2-dose schedule and 88.9%, 96.2%, 97.7% respectively for the 3-dose schedule). Overall, the persistence of the immune response until the booster at 11 months of age was lower in the 2-dose primed subjects. In both schedules, a booster response indicative of immunological priming was observed for each vaccine serotype (Table 7 and Table 8). After the booster dose a lower percentage of subjects with OPA titres  8 was observed in the 2-dose schedule for serotypes 5 (87.2% versus 97.5% for the 3-dose primed subjects) and 6B (81.1% versus 90.3%), all other responses were comparable.

Table 7: Percentage of 2-dose primed subjects with antibody concentrations ≥ 0.20 µg/ml one month post-primary and one month post-booster
 0.20 g/ml (ELISA)
Antibody               Post-primary                         Post-booster %               95% CI               %               95% CI
Anti-1        97.4        93.4        99.3         99.4        96.5        100 Anti-4        98.0        94.4        99.6         100         97.6        100 Anti-5        96.1        91.6        98.5         100         97.6        100 Anti-6B       55.7        47.3        63.8         88.5        82.4        93.0 Anti-7F       96.7        92.5        98.9         100         97.7        100 Anti-9V       93.4        88.2        96.8         99.4        96.5        100 Anti-14       96.1        91.6        98.5         99.4        96.5        100 Anti-18C       96.1        91.6        98.5         100         97.7        100 Anti-19F       92.8        87.4        96.3         96.2        91.8        98.6 Anti-23F       69.3        61.3        76.5         96.1        91.7        98.6 
Table 8: Percentage of 3-dose primed subjects with antibody concentrations ≥ 0.20 µg/ml one month post-primary and one month post-booster
 0.20 g/ml (ELISA)
Antibody               Post-primary                         Post-booster %               95% CI               %               95% CI
Anti-1        98.7        95.3        99.8         100         97.5        100 Anti-4        99.3        96.4         100         100         97.5        100 Anti-5        100         97.6         100         100         97.5        100 Anti-6B       63.1        54.8        70.8         96.6        92.2        98.9 Anti-7F       99.3        96.4         100         100         97.5        100 Anti-9V       99.3        96.4         100         100         97.5        100 Anti-14       100         97.6         100         98.6        95.2        99.8 Anti-18C       99.3        96.4         100         99.3        96.3        100 Anti-19F       96.1        91.6        98.5         98.0        94.2        99.6 Synflorix SPC V8.0 June 2020                     Page 14 of 21
Anti-23F         77.6        70.2         84.0           95.9       91.3         98.5 
For the cross-reactive serotype 19A, similar ELISA antibody GMCs were observed post-primary and post-booster for the 2-dose schedule [0.14 µg/ml (95% CI: 0.12; 0.17) and 0.73 µg/ml (95% CI: 0.58; 0.92)] and the 3-dose schedule [0.19 µg/ml (95% CI: 0.16; 0.24) and 0.87 µg/ml (95% CI: 0.69; 1.11)]. The percentage of subjects with OPA titres  8 and GMTs observed post-primary and post- booster were lower in the 2-dose schedule than that in the 3-dose schedule. In both schedules, a booster response indicative of immunological priming was observed.

The clinical consequences of the lower post-primary and post-booster immune responses observed after the 2-dose primary schedule are not known.

A clinical study conducted in South Africa assessed the immunogenicity of Synflorix after 3-dose (6- 10-14 weeks of age) or 2-dose (6-14 weeks of age) priming followed by a booster dose at 9-10 months of age. After primary vaccination, for the vaccine serotypes the percentages of subjects reaching antibody threshold and with OPA titres  8 were similar after 2-dose compared to 3-dose except lower OPA percentage for serotype 14. The antibody GMCs and OPA GMTs were lower after 2-dose for most vaccine serotypes.

For the cross-reactive serotype 19A, similar percentages of subjects reaching antibody threshold and OPA titres  8 and similar antibody GMC and OPA GMT were observed post-primary in both groups.
Overall, the pre-booster persistence of immune responses was lower in the 2-dose compared to the 3-dose priming group for most vaccine serotypes and was similar for serotype 19A.

Booster dose at 9–10 months of age

In the study conducted in South Africa, the booster dose given at 9-10 months of age induced marked increases in antibody GMCs and OPA GMTs for each vaccine serotype and serotype 19A in both 2- dose and 3-dose priming groups indicative of immunological priming.

Booster dose at 9–12 versus 15–18 months of age

A clinical study conducted in India assessing a booster dose given at 9-12 or 15-18 months of age in 66 and 71 children, respectively, following primary vaccination at 6, 10 and 14 weeks of age, did not suggest differences between groups in terms of antibody GMCs. Higher OPA GMTs in the group boosted at 15-18 months of age were observed for most of the vaccine serotypes and serotype 19A.
However, the clinical relevance of this observation is not known.


Immune memory

In the follow-up of the European study evaluating the 2-dose and 3-dose primary vaccination schedules, the persistence of antibodies at 36–46 months of age was demonstrated in subjects that had received a 2-dose primary series followed by a booster dose with at least 83.7% of subjects remaining seropositive for vaccine serotypes and the cross-reactive serotype 19A. In subjects that had received a 3-dose primary series followed by a booster dose, at least 96.5% of the subjects remained seropositive for vaccine serotypes and 86.4% for serotype 19A. After a single dose of Synflorix, administered during the 4th year of life, as a challenge dose, the fold increase in ELISA antibody GMCs and OPA GMTs, pre to post vaccination, was similar in 2-dose primed subjects to that in 3-dose primed subjects. These results are indicative of immunological memory in primed subjects for all vaccine serotypes and the cross-reactive serotype 19A.

Unvaccinated infants and children ≥ 7 months of age:

The immune responses elicited by Synflorix in previously unvaccinated older children were evaluated in three clinical studies.
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The first clinical study evaluated the immune responses for vaccine serotypes and the cross-reactive serotype 19A in children aged 7–11 months, 12–23 months and 2 to 5 years: 
•   Children aged 7–11 months received 2 primary doses followed by a booster dose in the second year of life. The immune responses after the booster dose in this age group were generally similar to those observed after the booster dose in infants who had been primed with 3 doses below 6 months of age.
•   In children aged 12–23 months, the immune responses elicited after two doses were comparable to the responses elicited after three doses in infants below 6 months of age, except for vaccine serotypes 18C and 19F as well as serotype 19A for which responses were higher in the 12–23 months children.
•   In children aged 2 to 5 years that received 1 dose, the ELISA antibody GMCs were similar for 6 vaccine serotypes as well as serotype 19A than those achieved following a 3-dose vaccination schedule in infants below 6 months of age while they were lower for              4 vaccine serotypes (serotypes 1, 5, 14 and 23F). The OPA GMTs were similar or higher following a single dose than a 3-dose primary course in infants below 6 months of age, except for serotype 5.

In the second clinical study, a single dose administered four months after two catch-up doses at 12–20 months of age elicited a marked increase of ELISA GMCs and OPA GMTs (when comparing the responses pre and post the last dose), indicating that two catch-up doses provide adequate priming.

The third clinical study showed that the administration of 2 doses with a 2 month interval starting at 36–46 months of age resulted in higher ELISA antibody GMCs and OPA GMTs than those observed one month after a 3-dose primary vaccination for each vaccine serotype and the cross-reactive serotype 19A. The proportion of subjects with an ELISA antibody concentration ≥ 0.20 µg/ml or an OPA titre ≥ 8 for each vaccine serotype was comparable or higher in the catch-up group than in the 3- dose primed infants.

Long-term persistence of antibodies has not been investigated after administration of a primary series in infants plus booster or after a 2-dose priming in older children.

In a clinical study, it has been demonstrated that Synflorix can be safely administered as a booster dose in the second year of life to children who had received 3 primary doses of 7-valent Prevenar. This study has shown that the immune responses against the 7 common serotypes were comparable to those elicited by a booster dose of 7-valent Prevenar. However, children who received 7-valent Prevenar for the primary series would not be primed against the additional serotypes contained in Synflorix (1, 5, 7F). Therefore the degree and duration of protection against invasive pneumococcal disease and otitis media due to these three serotypes in children of this age group following a single dose of Synflorix cannot be predicted.

Immunogenicity data in preterm infants

Immunogenicity of Synflorix in very preterm (gestation period of 27-30 weeks) (N=42), preterm (gestation period of 31-36 weeks) (N=82) and full term (gestation period > 36 weeks) (N=132) infants was evaluated following a 3-dose primary vaccination course at 2, 4, 6 months of age.
Immunogenicity following a fourth dose (booster dose) at 15 to 18 months of age was evaluated in 44 very preterm, 69 preterm and 127 full term infants.

One month after primary vaccination (i.e. after the third dose), for each vaccine serotype at least 92.7% of subjects achieved ELISA antibody concentrations ≥ 0.20 µg/ml and at least 81.7% achieved OPA titres ≥ 8 except serotype 1 (at least 58.8% with OPA titres ≥ 8). Similar antibody GMCs and OPA GMTs were observed for all infants except lower antibody GMCs for serotypes 4, 5, 9V and the cross-reactive serotype 19A in very preterms and serotype 9V in preterms and lower OPA GMT for serotype 5 in very preterms. The clinical relevance of these differences is not known.

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One month after the booster dose increases of ELISA antibody GMCs and OPA GMTs were seen for each vaccine serotype and the cross-reactive serotype 19A, indicative of immunological memory.
Similar antibody GMCs and OPA GMTs were observed for all infants except a lower OPA GMT for serotype 5 in very preterm infants. Overall, for each vaccine serotype at least 97.6% of subjects achieved ELISA antibody concentrations ≥ 0.20 µg/ml and at least 91.9% achieved OPA titres ≥ 8.

Immunogenicity in special population

HIV positive (HIV+/+) infants and HIV negative infants born from HIV positive mothers (HIV+/-) 
In a clinical study conducted in South Africa the immunogenicity of Synflorix administered as a 3-dose primary vaccination course (at 6, 10 and 14 weeks of age) followed by a booster dose (at 9 to 10 months of age) was assessed in 70 HIV positive (HIV+/+) infants, 91 HIV negative infants born from HIV positive mothers (HIV+/-) and 93 HIV negative infants born from HIV negative mothers (HIV-/-). Only HIV+/+ infants with WHO classification stage 1 (asymptomatic) or 2 (mild symptoms) were to be enrolled.

For most vaccine serotypes, group comparisons did not suggest any differences in post-primary immune responses between the HIV+/+ and HIV-/- groups, or the HIV+/- and HIV-/- groups, except for a trend towards a lower percentage of subjects reaching OPA titres ≥ 8 and lower OPA GMTs in the HIV+/+ group. The clinical relevance of this lower post-primary OPA response is not known. For the cross-reactive serotype 19A, the results did not suggest any differences in ELISA antibody GMCs and OPA GMTs between groups.

The booster dose of Synflorix in HIV+/+ and HIV+/- infants induced robust increases in ELISA antibody GMCs and OPA GMTs for each vaccine serotype and serotype 19A indicative of immunological priming. For most vaccine serotypes and serotype 19A, group comparisons did not suggest any differences post-booster dose in ELISA antibody GMCs and OPA GMTs between the HIV+/+ and HIV-/- groups, or the HIV+/- and HIV-/- groups.

The results for protein D suggested comparable post-primary and post-booster immune responses between groups.

In each group, persistence of the immune responses was observed at 24–27 months of age, i.e. up to 15 months following booster vaccination.

Children with sickle cell disease

A clinical study conducted in Burkina Faso assessed the immunogenicity of Synflorix administered to 146 children with SCD (haemoglobin SS disease, haemoglobin SC disease or with β-thalassemia) compared to 143 age-matched children without SCD. Among children with SCD, 48 children <6 months of age received primary vaccination at 8, 12 and 16 weeks of age, followed by a booster dose at 9–10 months of age, 50 children aged 7–11 months and 48 aged 12–23 months started catch-up vaccination according to their age. The immune response to Synflorix for each of the vaccine serotypes and serotype 19A, as well as for protein D, did not appear to be influenced by SCD.


Immunogenicity of Synflorix containing the preservative 2-phenoxyethanol (2-PE) 
Immunogenicity of Synflorix containing the preservative 2-PE (presented in a 4-dose container) was assessed in healthy infants vaccinated at 6, 10 and 18 weeks of age and compared to those receiving Synflorix without added preservative (160 enrolled subjects per group).

Immune responses were compared using non-inferiority criteria in terms of antibody GMC ratio (GMC from group of subjects receiving Synflorix without 2-PE over GMC from group of subjects receiving Synflorix with 2-PE) for each of the 10 vaccine serotypes and for the cross-reactive serotype 19A.
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Non-inferiority was demonstrated as the upper limit of the 2-sided 95% CI of the antibody GMC ratios was below 2 for each of the 10 vaccine serotypes and for serotype 19A. In addition, OPA GMTs were in same ranges for both groups.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Not applicable.