Pharmacotherapeutic group: pneumococcal vaccines.
ATC code: J07AL02.
Pharmacology: Pharmacodynamics: Mechanism of action: Prevenar 13 contains the 7 pneumococcal capsular polysaccharides that are in pneumococcal 7-valent conjugate vaccine (4, 6B, 9V, 14, 18C, 19F, 23F) plus 6 additional polysaccharides (1, 3, 5, 6A, 7F, 19A) all conjugated to CRM
197 carrier protein. B cells produce antibodies in response to antigenic stimulation via T-dependent and T-independent mechanisms. The immune response to most antigens is T-dependent and involves the collaboration of CD4+ T cells and B cells, recognizing the antigen in a linked fashion. CD4+ T cells (T-helper cells) provide signals to B cells directly through cell surface protein interactions, and indirectly through the release of cytokines. These signals result in proliferation and differentiation of the B cells, and production of high-affinity antibodies. CD4+ T cell signaling is a requisite for the generation of long-lived B cells called plasma cells, which continuously produce antibodies of several isotypes (with an IgG component) and memory B cells that rapidly mobilize and secrete antibodies upon re-exposure to the same antigen.
Bacterial capsular polysaccharides (PSs), while varied in chemical structure, share the common immunological property of being largely T-independent antigens. In the absence of T-cell help, PS-stimulated B-cells predominantly produce IgM antibodies; there is generally no affinity maturation of the antibodies, and no memory B cells are generated. As vaccines, PSs are associated with poor or absent immunogenicity in infants less than 24 months of age and failure to induce immunological memory at any age. Conjugation of PSs to a protein carrier overcomes the T-cell-independent nature of PS antigens. Protein carrier-specific T cells provide the signals needed for maturation of the B-cell response and generation of B-cell memory. Conversion of
S. pneumoniae PSs to a T-cell-dependent antigen by covalent coupling to the immunogenic protein carrier CRM
197 enhances the antibody response and induces immune memory. This has been demonstrated to elicit booster responses on re-exposure in infants and young children to pneumococcal polysaccharides.
Clinical trials data on efficacy: Disease Burden for Infants and Children:
S. pneumoniae is an important cause of morbidity and mortality in persons of all ages worldwide. The organism causes invasive infections, such as bacteremia and meningitis, as well as pneumonia and upper respiratory tract infections, including otitis media and sinusitis. In children older than 1 month,
S. pneumoniae is the most common cause of invasive disease. More than 90 different serotypes of
S. pneumoniae have been identified, varying both by the composition of their seroreactive capsular polysaccharides and in their ability to cause disease, with the majority of invasive disease caused by relatively few serotypes. The relative frequencies of pneumococcal serotypes causing invasive disease in children vary geographically, but have been remarkably stable over time.
Prior to the introduction of the pneumococcal 7-valent conjugate vaccine, the incidence of invasive pneumococcal disease (IPD) among children less than 2 years of age was approximately 180-200 cases/100,000/year, with an overall estimated case-fatality rate of 1.4%. The incidence of pneumococcal meningitis in this age group was estimated to be approximately 7-10 cases/100,000/year, with an associated mortality rate as high as 8%-25%. Of survivors, a significant proportion had serious sequelae, including developmental delay, seizure disorders, and deafness. Finally, while pneumonia is generally not considered to be invasive disease
per se, it may be accompanied by bacteremia or may be complicated by local invasion into a normally sterile space with empyema; both of these invasive manifestations of pneumonia are more severe and carry considerably higher morbidity and mortality rates than do non-invasive pneumonia, even among children. Prior to the licensure of the pneumococcal 7-valent conjugate vaccine, the estimated incidence of pneumonia among children <2 years of age was 24/100,000. Children in group child care have an increased risk for IPD, as do individuals with asthma, diabetes mellitus, immunocompromised individuals with neutropenia, asplenia, sickle cell disease, disorders of complement and humoral immunity, human immunodeficiency virus (HIV) infection or chronic underlying disease.
The exact contribution of
S. pneumoniae to childhood pneumonia is unknown, as it is often not possible to identify the causative organisms. In studies of children <5 years of age with community-acquired pneumonia (CAP), where diagnosis was attempted using serological methods, antigen testing, or culture data, 30% of cases were classified as bacterial pneumonia, and 70% of these (21% of total CAP) were found to be due to
S. pneumoniae, making it the most common bacterial cause of pneumonia in this age group. Observations since the introduction of the pneumococcal 7-valent conjugate vaccine, however, suggest that
S. pneumoniae, and in particular those pneumococcal serotypes included in the vaccine, are responsible for a considerable burden of CAP among children, and that the pneumococcal 7-valent conjugate vaccine is effective in preventing CAP in children. While uncomplicated pneumonia is generally considered non-invasive disease, pneumococcal pneumonia may be complicated by both bacteremia and locally invasive manifestations, including pleural empyema and pulmonary necrosis.
Burden of disease in infants and children aged 6 weeks to 5 years: Acute otitis media (AOM) is a common childhood disease with different aetiologies. Bacteria can be responsible for 60%-70% of clinical episodes of AOM.
S. pneumoniae is one of the most common causes of bacterial AOM worldwide.
S. pneumoniae is also a major cause of non-invasive disease in children, particularly of acute otitis media (AOM). AOM is a common childhood disease, with more than 60% of children experiencing an episode by 1 year of age, and more than 90% of children experiencing an episode by age 5. The peak incidence of AOM is 6-18 months of age. Otitis media is less common, but occurs, in older children. Complications of AOM include persistent middle-ear effusion, chronic otitis media, transient hearing loss, or speech delays and, if left untreated, may lead to more serious diseases, such as mastoiditis and meningitis.
S. pneumoniae is an important cause of AOM. It is the bacterial pathogen most commonly isolated from middle-ear fluid, identified in 20%-40% of middle-ear fluid cultures in AOM. Pneumococcal otitis media is associated with higher rates of fever and is less likely to resolve spontaneously than AOM due to either non-typeable
H. influenzae or
M. catarrhalis.
Prevenar 13 is estimated to cover over 90% of serotypes causing antibiotic-resistant IPD.
Burden of disease in 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 co-morbidities.
Disease Burden for Adults:
S. pneumoniae is a significant threat to world health. The World Health Organization (WHO) estimates that each year 1.6 million people die from pneumococcal disease, of which 600,000 to 800,000 are adults. Pneumococcal disease can be classified by the degree of bacterial invasion, which is predictive of complications and mortality. IPD is defined by the isolation of pneumococcus from a normally sterile site, such as blood, cerebrospinal fluid, pleural fluid, or peritoneal fluid. In adults, the major clinical presentations of IPD are meningitis, bacteremia, or bacteremic pneumonia. Pneumonia without bacteremia is the most common serious manifestation of non-IPD.
Burden of disease in adults aged 50 years and older: The incidence of invasive pneumococcal disease (IPD) in adults increases with age from 50 years, risk factors (smoking status or alcohol use), and underlying co-morbidities (chronic cardiovascular disease, chronic pulmonary disease including asthma, renal disorders, diabetes mellitus, and chronic liver disease including alcoholic liver disease). Bacteraemic pneumonia, bacteraemia without a focus, and meningitis are the most common manifestations of IPD in adults aged 50 years or older. Based on surveillance data, the pneumococcal serotypes in Prevenar 13 may be responsible for at least 50% - 76% (depending on country) of IPD in adults aged over 50 years. Approximately 80% of IPD in adults is bacteraemic pneumonia.
Adults older than 50 years of age, especially those older than 65 years of age, are at increased risk for developing pneumococcal infections and are more likely to develop IPD with its associated increased mortality, morbidity and complications. Additional risk factors for serious pneumococcal disease include living circumstances and underlying medical conditions which may also concern younger adults, e.g., 18 years and above. Living conditions can increase the individual risk of pneumococcal disease, particularly residence in a nursing home or other long-term care facility. Significant medical risk conditions include: congenital or acquired immunodeficiency; sickle cell disease; asplenia; human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS); malignant hematological diseases, chronic heart, lung (including asthma), renal, or liver diseases; cancer; cerebrospinal fluid (CSF) leak; diabetes; chronic alcoholism or cigarette smoking; organ or hematopoietic cell transplantation; and cochlear implants. Despite advances in medical science over the last decades, there has been little change in mortality rates since penicillin's introduction.
Pneumonia is one of the most common infectious diseases and the most common clinical presentation of pneumococcal disease in adults.
S. pneumoniae is the most frequent cause of CAP, and is estimated to be responsible for approximately 30% of all CAP cases requiring hospitalization in adults in developed countries. The incidence of non-bacteremic pneumonia caused by
S. pneumoniae is difficult to ascertain, because the causative pathogen is not identified in the majority of cases. Mortality from all-cause CAP range from 5%-15% and CAP contributes to a significant proportion of intensive care unit (ICU) admissions. Patients with pneumonia caused by
S. pneumoniae tend to have more severe illness including greater likelihood of bacteremia, longer hospitalization, greater need for intensive care, and higher mortality. As for IPD, the risk of pneumococcal pneumonia increases with age from 50 years and is highest in individuals aged ≥65 years of age. Risk 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 those with malignant haematological diseases or HIV infection.
While host factors, such as age and comorbid conditions contribute to the likelihood of IPD and poor outcomes, there has been increasing appreciation that pathogen virulence and antimicrobial resistance play an important role. Although more than 90 different serotypes of
S. pneumoniae have been identified, human disease is caused by a relatively small group of serotypes possessing poorly defined virulence factors that allow them to cause disease. According to a meta-analysis of serotype-specific disease outcomes for patients with pneumonia, serotypes 3, 6A, 6B, 9N, and 19F were statistically significantly associated with increased mortality when compared to serotype 14, used as a reference. For serotypes 19A and 23F, there was a trend towards increased mortality which did not reach statistical significance. Despite some regional variations in rate and mortality, these observations appeared to be a relatively stable characteristic of the serotype and appeared to be independent of antimicrobial resistance.
Antimicrobial resistance increases the difficulty of initially treating some serotypes of
S. pneumoniae with an effective antibiotic. Despite great geographic variability of serotype distribution and prevalence of antimicrobial resistance, serotypes 6A, 6B, 9V, 14, 15A, 19F, 19A and 23F were most likely to demonstrate resistance to both penicillin and erythromycin.
Prevenar 13 provides an immune response against prevalent strains of
S. pneumoniae including those most likely to cause disease, be antimicrobial resistant, and result in poor outcomes. (See Table 1.)
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Prevenar 13 Immunogenicity Clinical Studies in Infants and Children: The protective efficacy of Prevenar 13 against IPD has not been studied. The World Health Organization (WHO) has recommended a serum anti-capsular polysaccharide antibody concentration of 0.35 μg/mL measured 1 month after the primary infant series as a single antibody reference concentration to estimate the efficacy of new pneumococcal conjugate vaccines against IPD. This recommendation is largely based upon the observed correlation between immunogenicity and IPD efficacy from 3 placebo-controlled trials with either pneumococcal 7-valent conjugate vaccine or the investigational 9-valent CRM
197 conjugate polysaccharide vaccine. This reference concentration is only applicable on a population basis and cannot be used to predict protection against IPD on an individual basis.
Immune responses following a 3-dose primary infant series: Clinical trials have been conducted in a number of European countries, Canada and the US using a range of primary vaccination schedules, including two randomized non-inferiority studies (Germany [006] and US [004]). In these two studies, the immune responses were compared using a set of non-inferiority criteria including the percentage of subjects with serum anti-polysaccharide serotype specific IgG ≥0.35 μg/mL 1 month after the primary series and the comparison of IgG geometric mean concentrations (ELISA GMC in addition, functional antibody titres (OPA) between subjects receiving Prevenar 13 and Prevenar were compared. For the six additional serotypes, these values were compared with the lowest response among all of the common serotypes in the Prevenar recipients.
The non-inferiority immune response comparisons for study 006 based on the proportion of infants achieving anti-polysaccharide IgG concentrations ≥0.35 μg/mL, are shown in Table 2 as follows. Results for study 004 were similar. Prevenar 13 non-inferiority (lower bound of the 95% CI for the difference in percentage of responders at 0.35 μg/mL between groups was >-10%) was demonstrated for all 7 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 criteria for 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 achieving antibody concentrations ≥0.35 μg/mL and comparison of IgG ELISA GMCs in study 006 and was met for 5 out of the 6 serotypes, with the exception of serotype 3 for study 004. For serotype 3, the percentage of Prevenar 13 recipients with serum IgG ≥0.35 μg/mL were 98.2% (study 006) and 63.5% (study 004). (See Table 2.)
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Prevenar 13 elicited functional antibodies to all 13 vaccine serotypes in studies 004 and 006. For the 7 common serotypes, there were no differences between groups in the proportion of subjects with OPA titres ≥1:8. For each of the seven common serotypes, >96% and >90% of the Prevenar 13 recipients reached 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% of vaccines 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 other additional serotypes; the clinical relevance of this observation for protective efficacy is unknown.
The percentage of infants achieving pneumococcal anti-capsular polysaccharide IgG antibody concentrations ≥0.35 μg/mL 1 month after a 3-dose primary series in representative studies are presented as follows (Table 3). (See Table 3.)
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In Prevenar 13 recipients, anti-polysaccharide binding IgG antibody for each of the 13 serotypes has been demonstrated to be correlated with functional antibacterial opsonophagocytic activity (biologically active antibody). Clinical trials also demonstrated that the response to Prevenar 13 was non-inferior to that of pneumococcal 7-valent conjugate vaccine for all 13 serotypes using a set of pre-defined immunological non-inferiority criteria. Immune responses elicited by Prevenar 13 to the 6 additional serotypes were quantitatively greater, for both polysaccharide-binding and opsonophagocytic antibodies, than the responses elicited by pneumococcal 7-valent conjugate vaccine.
Immune responses following a 2-dose infant primary series:
The immunogenicity after 2 doses in infants has been documented in 4 studies. The proportion of infants achieving a pneumococcal anti-capsular polysaccharide IgG concentration ≥0.35 μg/mL 1 month 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 58.4%) and 23F (55.8% to 68.6%) 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, all vaccine serotypes including 6B and 23F had immune responses consistent with adequate priming with a 2-dose primary series. In a UK study, the functional antibody (OPA) responses were comparable for all serotypes including 6B and 23F in the Prevenar and Prevenar 13 arms after the primary series at two 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, and at least 93% following the booster dose. The OPA geometric mean titres for serotypes 1, 3 and 5 were lower than the titres for each of the other additional serotypes; the clinical relevance of this observation is unknown. Compared to a 3-dose infant series, pneumococcal anti-capsular polysaccharide IgG GMCs were lower after a 2-dose infant series for most serotypes. The clinical effectiveness of a 2-dose primary series against AOM or pneumonia has not been established.
Booster responses following 2-dose and 3-dose primary infant series:
Following the booster dose, antibody concentrations increased from the pre-booster level for all 13 serotypes. Post-booster antibody concentrations were higher for 12 serotypes than those achieved after the infant primary series. These observations are consistent with adequate priming (the induction of immunologic memory). For serotype 3, antibody concentrations following the infant primary series and booster dose were similar; the clinical relevance of this observation regarding the induction of serotype 3 immune memory is unknown.
Antibody responses to booster doses following 2-dose or 3-dose infant primary series were comparable for all 13 vaccine serotypes.
For children aged 7 months to 5 years, age appropriate catch-up immunisation schedules (as described in Dosage & Administration) result in levels of anti-capsular polysaccharide IgG antibody responses to each of the 13 serotypes that are at least comparable to those of a 3-dose primary series in infants.
Antibody persistence and immunological memory were evaluated in a study in healthy children who received a single dose of Prevenar 13 at least 2 years after they had been previously immunised with either 4 doses of Prevenar, a 3-dose infant series of Prevenar followed by Prevenar 13 at 12 months of age, or 4 doses of Prevenar 13.
The single dose of Prevenar 13, in children approximately 3.4 years of age regardless of previous vaccination history with Prevenar or Prevenar 13, induced a robust antibody response for both the 7 common serotypes and the 6 additional serotypes in Prevenar 13.
Since the introduction of 7-valent Prevenar in 2,000, pneumococcal disease surveillance data have not shown that the immunity elicited by Prevenar in infancy has waned over time.
Booster Responses to Prevenar 13 Following a 3-Dose Primary Infant Series of Pneumococcal 7-valent Conjugate Vaccine or Prevenar 13: In a randomized, double-blind, active-control study in France (6096A1-008) infants were randomly assigned to 3 groups in a 2:1:1 ratio: (1) Prevenar 13 at 2, 3, 4 and 12 months or (2) pneumococcal 7-valent conjugate vaccine at 2, 3, and 4 months followed by Prevenar 13 at 12 months or (3) pneumococcal 7-valent conjugate vaccine at 2, 3, 4 and 12 months. Geometric mean concentrations of anti-capsular polysaccharide IgG antibody responses to each of the 13 serotypes in the 3 groups are shown in Table 4. GMCs to the 7 pneumococcal 7-valent conjugate vaccine serotypes did not differ in the 3 groups. Although the GMCs to the 6 additional serotypes in the pneumococcal 7-valent conjugate vaccine/Prevenar 13 recipients were lower than those observed with the 4-dose Prevenar 13 regimen (except for serotype 3), they were at least comparable to those of a 3-dose primary series in infants in studies (6096A1-004) and (6096A1-3005). This comparison to infant series responses is similar to what was done with pneumococcal 7-valent conjugate vaccine to establish the immunization schedules in older infants and children. (See Table 4.)
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Preterm Infants (B1851037 [6096A1-4001]): Safety and immunogenicity of Prevenar 13 given at 2, 3, 4 and 12 months was assessed in 100 prematurely born infants (Estimated Gestational Age [EGA] mean, 31 weeks; range, 26 to 36 weeks) and compared with 100 infants born at term (EGA mean, 39 weeks; range, 37 to 42 weeks). More than 85% of subjects in the preterm group in the evaluable immunogenicity population achieved a pneumococcal polysaccharide IgG binding antibody concentration ≥0.35 µg/mL 1 month after the infant series for all serotypes except serotypes 5 (71.7%), 6A (82.7%), and 6B (72.7%) in the preterm group. For these 3 serotypes, the proportion of responders among preterm infants was significantly lower than among term infants. One month after the toddler dose, evidence of priming was observed as the proportion of subjects in each group in the evaluable toddler immunogenicity population achieving this same antibody concentration threshold was >97%, except for serotype 3 (70.6% in preterm infants and 79.3% in term infants). In general, serotype-specific IgG GMCs were lower for preterm infants than term infants.
During study B1851037, immune response to concomitantly administered vaccines was not assessed and therefore, data are not available from this study.
Prevenar (7-valent vaccine) protective efficacy in infants and children: The efficacy of the pneumococcal 7-valent conjugate vaccine against otitis media was assessed in 2 clinical trials: a trial in Finnish infants at the National Public Health Institute and the pivotal efficacy trial in US infants at Northern California Kaiser Permanente (NCKP). The Finnish Otitis Media (FinOM) trial was a randomized, double-blind trial in which 1,662 infants were equally randomized to receive either pneumococcal 7-valent conjugate vaccine or a control vaccine (Hepatitis B vaccine [Hep B]) at 2, 4, 6, and 12-15 months of age. In this study, parents of study participants were asked to bring their children to the study clinics if the child had respiratory infection or symptoms suggesting AOM. If AOM was diagnosed, tympanocentesis was performed, and the middle-ear fluid was cultured. If
S. pneumoniae was isolated, serotyping was performed; the primary endpoint was efficacy against AOM episodes caused by vaccine serotypes in the per-protocol population. In the NCKP trial, the efficacy of the pneumococcal 7-valent conjugate vaccine against otitis media was assessed from the beginning of the trial in October 1995 through April 1998. The otitis media analysis included 34,146 infants randomized to receive either the pneumococcal 7-valent conjugate vaccine (N = 17,070), or the control vaccine (N = 17,076), at 2, 4, 6, and 12-15 months of age. In this trial, no routine tympanocentesis was performed, and no standard definition of otitis media was used by study physicians. The primary otitis media endpoint was efficacy against all otitis media episodes in the per-protocol population.
The vaccine efficacy against AOM episodes due to vaccine serotypes assessed in the Finnish trial was 57% (95% CI, 44%-67%) in the per-protocol population and 54% (95% CI, 41%-64%) in the intent-to-treat population. The vaccine efficacy against AOM episodes due to vaccine-related serotypes (6A, 9N, 18B, 19A, 23A), also assessed in the Finnish trial, was 51% (95% CI, 27, 67) in the per-protocol population and 44% (95% CI, 20, 62) in the intent-to-treat population. There was a non-significant increase in AOM episodes caused by serotypes unrelated to the vaccine in the per-protocol population, suggesting that children who received the pneumococcal 7-valent conjugate vaccine appeared to be at increased risk of otitis media due to pneumococcal serotypes not represented in the vaccine, compared to children who received the control vaccine. However, vaccination with the pneumococcal 7-valent conjugate vaccine reduced pneumococcal otitis media episodes overall. In the NCKP trial, in which the endpoint was all otitis media episodes regardless of etiology, vaccine efficacy was 7% (95% CI, 4%-10%) and 6% (95% CI, 4%-9%), respectively, in the per-protocol and intent-to-treat analyses. Several other otitis media endpoints were also assessed in the 2 trials. Recurrent AOM, defined as 3 episodes in 6 months or 4 episodes in 12 months, was reduced by 9% in both the per-protocol and intent-to-treat populations (95% CI, 3%-15% in per-protocol and 95% CI, 4%-14% in intent-to-treat) in the NCKP trial; a similar trend was observed in the Finnish trial. The NCKP trial also demonstrated a 20% reduction (95% CI, 2, 35) in the placement of tympanostomy tubes in the per-protocol population and a 21% reduction (95% CI, 4, 34) in the intent-to-treat population. Data from the NCKP trial accumulated through an extended follow-up period to April 20, 1999, in which a total of 37,866 children were included (18,925 in the pneumococcal 7-valent conjugate vaccine group and 18,941 in the MnCC control group), resulted in similar otitis media efficacy estimates for all endpoints.
The efficacy results from these trials (for invasive pneumococcal disease, pneumonia, and acute otitis media) are presented as follows (Table 5). (See Table 5.)
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Similar to the experience with IPD, reductions in AOM have been observed in the US since the introduction of the pneumococcal 7-valent conjugate vaccine as a routine infant vaccine. Since diagnostic tympanocentesis is not routinely performed in the US, less information is available on shifts in the distribution of causative pneumococcal serotypes. However, results of several recent studies suggest that non-pneumococcal 7-valent conjugate vaccine serotypes are also emerging as important causes of AOM or its complications in children (including mastoiditis, which now accounts for 12% of all IPD in the US Pediatric Multicenter Pneumococcal Surveillance Study, all of it caused in 2006-2007 by serotype 19A, and that these non-pneumococcal 7-valent conjugate vaccine serotypes are likely to be resistant to commonly used antimicrobial agents. Another series of pneumococcal isolates from tympanocentesis samples collected from 5 centers across the United States identified serotype 3 most commonly, with a smaller percentage accounted for by serotypes 1 and 7.
Prevenar (7-valent) effectiveness: The effectiveness (both direct and indirect effect) of 7-valent Prevenar against pneumococcal disease has been evaluated in both three-dose and two-dose primary infant series immunisation programmes, each with booster doses (Table 6). Following the widespread use of Prevenar, the incidence of IPD has been consistently and substantially reduced. An increase in the incidence of IPD cases caused by serotypes not contained in Prevenar, such as 1, 7F and 19A, has been reported in some countries. Surveillance will continue with Prevenar 13, and as countries update their surveillance data, information in this table may change.
Using the screening method, serotype specific effectiveness estimates for 2 doses under the age of 1 year in the UK were 66% (29, 91%) and 100% (25, 100%) for serotype 6B and 23F, respectively. (See Table 6.)
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Effectiveness of Prevenar in a 3+1 schedule has also been observed against acute otitis media and pneumonia since its introduction in a national immunisation programme. In a retrospective evaluation of a large US insurance database, AOM visits were reduced by 42.7%, and prescriptions for AOM by 41.9%, in children younger than 2 years of age, compared with a pre-licensure baseline (2004 vs. 1997-99). In a similar analysis, hospitalisations and ambulatory visits for all-cause pneumonia were reduced by 52.4% and 41.1%, respectively. For those events specifically identified as pneumococcal pneumonia, the observed reductions in hospitalisations and ambulatory 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 be inferred from observational analyses of this type, these findings suggest that Prevenar plays an important role in reducing the burden of mucosal disease (AOM and pneumonia) in the target population.
Previously unvaccinated older infants and children: In an open-label study of Prevenar 13 in Poland (6096A1-3002), children 7-11 months of age, 12-23 months and ≥24 months to 5 years of age (prior to the 6
th birthday) who were naive to pneumococcal conjugate vaccine, were given 3, 2 or 1 dose of Prevenar 13 according to the age appropriate schedules (see Dosage & Administration). Serum IgG concentrations were measured 1 month after the final dose in each age group and the data are shown in Table 7.
These age appropriate catch-up immunisation schedules result in levels of anti-capsular polysaccharide IgG antibody responses to each of the 13 serotypes that are at least comparable to those of a 3-dose primary series in infants. (See Table 7.)
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Simultaneous administration with other vaccines in infants and children: In studies 6096A1-004, 6096A1-3005, and 6096A1-3008, routine pediatric vaccines were administered at the same visit as Prevenar 13. Immune responses to selected concomitant vaccine antigens were compared in infants receiving pneumococcal 7-valent conjugate vaccine and Prevenar 13. The proportion of responders at pre-specified antibody levels are shown in Table 8. Responses to all antigens in Prevenar 13 recipients were similar to those in pneumococcal 7-valent conjugate vaccine recipients and met formal criteria for non-inferiority. Varicella responses as measured by a commercial whole cell ELISA kit, designed to detect immunity after natural infection, were low in both groups, but there was no evidence of interference with the immune response by concomitantly administered Prevenar 13. (See Table 8.)
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Additional Prevenar (7-valent) immunogenicity data: children with sickle cell disease:
The immunogenicity of Prevenar has been investigated in an open-label, multicenter study in 49 infants with sickle cell disease. Children were vaccinated with Prevenar (3 doses one month apart from the age of 2 months), and 46 of these children also received a 23-valent pneumococcal polysaccharide vaccine at the age of 15-18 months. After primary immunisation, 95.6% of the subjects 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 the polysaccharide vaccination, suggesting that immunological memory was well established.
Children and adolescents 5-17 years of age:
In Study 6096A1-3011 in the US, in children 5 to <10 years of age previously vaccinated with at least 1 dose of pneumococcal 7-valent conjugate vaccine, and in pneumococcal vaccine-naïve children and adolescents 10-17 years of age 1 dose of Prevenar 13 elicited immune responses to all 13 serotypes.
In children 5 to <10 years of age, serum IgG concentrations for the 7 common serotypes 1 month after administration of a single dose of Prevenar 13 vaccination (Study 6096A1-3011) were non-inferior (i.e., the lower limit of the 2-sided 95% CI for the geometric mean ratio [GMR] of >0.5) to those elicited by the fourth dose of pneumococcal 7-valent conjugate at 12-15 months of age (Study 6096A1-3005). In addition, IgG concentrations elicited by a single dose of Prevenar 13 for the 6 additional serotypes in children 5 to <10 years of age were non-inferior to those elicited by the fourth dose of Prevenar 13 at 12-15 months of age (Study 6096A1-3005) as shown in Tables 9 and 10. (See Tables 9 and 10.)
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In children and adolescents 10 to 17 years of age OPA GMTs 1 month after vaccination were non-inferior (i.e., the lower limit of the 2-sided 95% CI for the GMR of >0.5) to OPA GMTs in the 5 to <10 year-old group for 12 of the 13 serotypes (except for serotype 3), as shown in Table 11. (See Table 11.)
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Prevenar 13 Effectiveness: Invasive Pneumococcal Disease: Four years after the introduction of Prevenar as a two dose primary series plus booster dose in the second year of life and with a 94% vaccine uptake a 98% (95% CI 95; 99) reduction of disease caused by the 7 vaccine serotypes was reported in England and Wales. Subsequently, four years following the switch to Prevenar 13, the additional reduction in incidence of IPD due to the 7 serotypes in Prevenar ranged from 76% in children less than 2 years of age to 91% in children 5-14 years of age. The serotype specific reductions for each of the 5 additional serotypes in Prevenar 13 (no cases of serotype 5 IPD were observed) by age group are shown in Table 12 and ranged from 68% (serotype 3) to 100% (serotype 6A) for children less than 5 years of age. Significant incidence reductions were also observed in older age groups who had not been vaccinated with Prevenar 13 (indirect effect). (See Table 12.)
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Otitis Media (OM): In a two dose primary series plus booster dose in the second year of life the impact of Prevenar 13 on OM was documented in a population based active surveillance system in Israel with tympanocentesis culturing of middle ear fluid in children less than 2 years of age with OM. Following the introduction of pneumococcal 7-valent conjugate vaccine and subsequently Prevenar 13 there was a decline in incidence of 96% of OM for the pneumococcal 7-valent conjugate vaccine serotypes plus serotype 6A and a decline in incidence of 85% for the additional serotypes 1, 3, 5, 7F, and 19A in Prevenar 13.
In a prospective, population-based, long-term surveillance study conducted in Israel between 2004 and 2015 following the introduction of pneumococcal 7-valent conjugate vaccine and subsequently Prevenar 13, reductions of non-pneumococcal bacteria isolated from children <3 years of age with OM were 75% for all NTHi cases, and 81% and 62% for cases of OM due to
M. catarrhalis and
S. pyogenes, respectively.
Pneumonia: In a multicenter observational study in France comparing the periods before and after the switch from pneumococcal 7-valent conjugate vaccine to Prevenar 13, there was 16% reduction in all community acquired pneumonia (CAP) cases in emergency departments in children 1 month to 15 years of age. Reductions were 53% (p<0.001) for CAP cases with pleural effusion and 63% (p<0.001) for microbiologically confirmed pneumococcal CAP cases. In the second year after the introduction of Prevenar 13 the total number of CAP cases due to the 6 additional vaccine serotypes in Prevenar 13 was reduced by 74% (27 to 7 isolates).
In an ongoing surveillance system (2002 to 2013) to document the impact of pneumococcal 7-valent conjugate vaccine and subsequently Prevenar 13 on CAP in children less than 5 years in Southern Israel using a 2 dose primary 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 the introduction of Prevenar 13 when compared to the period before the introduction of pneumococcal 7-valent conjugate vaccine was introduced.
While direct cause-and-effect cannot be inferred from observational analyses of this type, these findings suggest that Prevenar plays an important role in reducing the burden of mucosal disease (AOM and pneumonia) in the target population.
Reduction of Antimicrobial Resistance (AMR): Following the introduction of pneumococcal 7-valent conjugate vaccine and subsequently Prevenar 13, a reduction in AMR has been shown as a result of direct reduction of serotypes and clones associated with AMR from the population (including 19A), reduction of transmission (herd effects), and reduction in the use of antimicrobial agents.
In a double-blind, randomized, controlled study in Israel comparing pneumococcal 7-valent conjugate vaccine and Prevenar 13 that reported the acquisition of
S. pneumoniae, reductions of serotypes 19A, 19F, and 6A not susceptible to either penicillin, erythromycin, clindamycin, penicillin plus erythromycin, or multiple drugs (≥3 antibiotics) ranged between 34% and 62% depending on serotype and antibiotic.
Analyses of data from the United States Centers for Disease Control and Prevention evaluated temporal trends for four antibiotic classes and showed that compared to 2009 (the last year of pneumococcal 7-valent conjugate vaccine use in the US, following which it was replaced with Prevenar 13), by 2013 the annual incidence of IPD due to pneumococci non-susceptible to macrolides, cephalosporins, penicillins, and tetracyclines had decreased by 63%, 81%, 83%, and 81% in children less than 5 years of age and 24%, 49%, 57%, and 53% in persons 65 years of age and older.
Prevenar 13 Effect on Nasopharyngeal Carriage: In a surveillance study in France in children presenting with AOM, changes in nasopharyngeal (NP) carriage of pneumococcal serotypes were evaluated following the introduction of pneumococcal 7-valent conjugate vaccine and subsequently Prevenar 13. Prevenar 13 significantly reduced NP carriage of the 6 additional serotypes (and serotype 6C) combined and individual serotypes 6C, 7F, 19A when compared with pneumococcal 7-valent conjugate vaccine. 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 or 5 observed.
The effect of pneumococcal conjugate vaccination on NP carriage was studied in a randomized double-blind study (6096A1-3006) in which infants received either Prevenar 13 or pneumococcal 7-valent conjugate vaccine at 2, 4, 6 and 12 months of age in Israel. Prevenar 13 significantly reduced newly identified NP acquisition of the 6 additional serotypes (and serotype 6C) combined and of individual serotypes 1, 6A, 6C, 7F, 19A when compared with pneumococcal 7-valent conjugate vaccine. There was no reduction seen in serotype 3 and for serotype 5 the colonization was too infrequent to assess impact. For 6 of the remaining 7 common serotypes, similar rates of NP acquisition were observed in both vaccine groups; for serotype 19F a significant reduction was observed.
Efficacy Study in Adults 65 Years and Older: Efficacy against vaccine type (VT) pneumococcal CAP and IPD was assessed in a large-scale randomised 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 single vaccination of either Prevenar 13 or placebo in a 1:1 randomization.
The CAPiTA study enrolled volunteers ≥65 years of age whose demographic and health characteristics may differ from those seeking vaccination.
Efficacy of Prevenar 13 in preventing a first episode of VT pneumococcal CAP (the primary endpoint of the study) and the two secondary endpoints was demonstrated as shown in Table 13. (See Table 13.)
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The protective efficacy of Prevenar 13 against a first episode of VT pneumococcal CAP, VT NB/NI pneumococcal CAP, and VT-IPD was evident shortly after vaccination and was sustained throughout the duration of the study.
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 or etiologic confirmation): vaccine efficacy, incidence rate reduction and number needed to vaccinate (Table 14): see Table 14.
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Although CAPiTA was not powered to demonstrate serotype specific VE, an evaluation of clinical CAP data was performed for serotypes with at least 10 outcomes in the placebo group. VE (95% CI) for the five evaluated serotypes against first clinical CAP episodes were: serotype 1, 20.0% (-83.1% to 65.8%); serotype 3, 61.5% (17.6% to 83.4%); serotype 6A, 33.3% (-58.6% to 73.2%); serotype 7F, 73.3% (40.5% to 89.4%); and serotype 19A, 45.2% (-2.2% to 71.5%).
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.
Prevenar 13 Immunogenicity Clinical Trials in Adults: An anti-polysaccharide binding antibody IgG level to predict protection against IPD or non-bacteremic pneumonia has not been defined for adults. However, non-clinical and clinical data support functional antibody, measured by OPA assay, as a contributor to protection against pneumococcal disease. OPA provides an
in vitro measurement of the ability of serum antibodies to eliminate pneumococci by promoting complement-mediated phagocytosis and is believed to reflect relevant
in vivo mechanisms of protection against pneumococcal disease. OPA titers are expressed as the reciprocal of the highest 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 Prevenar 13 serotypes are non-inferior and for some serotypes superior to the common serotypes in the currently licensed PPSV23.
Serotype-specific OPA geometric mean titers (GMTs) measured 1 month after each vaccination were calculated. Non-inferiority between vaccines was defined as the lower bound of the 2-sided, 95% confidence interval (CI) for the ratio of the GMTs (GMR) >0.5 (2-fold criterion); statistically significantly greater responses were defined as the lower bound of the 2-sided 95% CI for the GMR >1.
The response to the additional serotype 6A, which is unique to Prevenar 13 but not in PPSV23 was assessed by demonstration of a 4-fold increase in the specific OPA titer above pre-immunization levels. Superiority of the response for Prevenar 13 was defined as the lower bound of the 2-sided, 95% CI for the difference in percentages of adults achieving a 4-fold increase in OPA titer greater than zero. For comparison of OPA GMTs, a statistically greater response for serotype 6A was defined as the lower bound of the 2-sided 95% CI for the GMR >2.
Five (5) Phase 3 clinical trials (6115A1-004, 6115A1-3005, 6115A1-3010, 6115A1-3001, 6115A1-3008) were conducted in a number of European countries and in the US evaluating the immunogenicity of Prevenar 13 in different age groups, and in individuals who were either not previously vaccinated (PPSV23 unvaccinated) with PPSV23 or had received 1 or more doses of PPSV23 (PPSV23 pre-vaccinated).
Each study included healthy adults and immunocompetent adults with stable underlying conditions including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease including alcoholic liver disease, and alcoholism because it is known that these are common conditions in adults that increase risk of serious pneumococcal CAP and IPD.
Two (2) pivotal non-inferiority trials were conducted in which Prevenar 13 response was compared to PPSV23 immune response, 1 in PPSV23 unvaccinated adults aged 50-64 years (6115A1-004), and 1 in PPSV23 pre-vaccinated adults aged ≥70 years (6115A1-3005). One (1) study (6115A1-3000) in PPSV23 pre-vaccinated adults collected safety data only. Two (2) studies (6115A1-3001 and 6115A1-3008) assessed the concomitant administration of Prevenar 13 with seasonal TIV.
Clinical trials conducted in adults not previously vaccinated with PPSV23: In an active-controlled modified
1 double-blind clinical trial (6115A1-004) of Prevenar 13 in the US, PPSV23-unvaccinated adults aged 60-64 years were randomly assigned (1:1) to receive Prevenar 13 or PPSV23. In addition, adults aged 18-49 years (with age sub-groups 18-29 years, 30-39 years, 40-49 years) and 50-59 years were enrolled and received 1 dose of Prevenar 13 (open-label).
The OPA antibody responses elicited by Prevenar 13 were non-inferior to those elicited by PPSV23 for the 12 serotypes in common to both vaccines. In addition, 8 of the serotypes in common exhibited a statistically significantly greater immune response after Prevenar 13 compared with after PPSV23.
For serotype 6A, which is unique to Prevenar 13, the proportions of adults with a 4-fold increase after Prevenar 13 (88.5%) were significantly greater than after PPSV23 (39.2%) in PPSV23-unvaccinated adults aged 60-64 years. OPA GMTs for serotype 6A were statistically significantly greater after Prevenar 13 compared with after PPSV23.
The OPA responses elicited by Prevenar 13 in adults aged 50-59 years were non-inferior to the Prevenar 13 responses in adults aged 60-64 years for all 13 serotypes. In addition, 9 of the 13 serotypes exhibited a statistically significantly greater immune response in adults aged 50-59 years compared with adults aged 60-64 years.
This clinical trial demonstrated that the immune responses elicited by Prevenar 13 are non-inferior and for most serotypes statistically significantly greater than PPSV23. In addition, the immune responses in adults aged 50-59 years were non-inferior and for most serotypes statistically significantly greater than those observed in adults aged 60-64 years.
1Modified double-blind means that the site staff dispensing and administering the vaccine were unblinded, but all other study personnel including the principal investigator and subject were blinded.
In adults aged 60-64 years, antibody levels 1 year after vaccination were greater after Prevenar 13 compared to antibody levels after PPSV23 for 7 of 12 serotypes in common. In adults aged 50-59 years, antibody levels one year after vaccination with Prevenar 13 were greater for 12 of 13 serotypes compared to vaccination with Prevenar 13 in 60-64 years old. (See Table 15.)
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Table 16 shows OPA GMTs 1-month after vaccination in subjects 18-29 years of age, 30-39 years of age, and 40-49 years of age given a single dose of Prevenar 13. It also shows a comparison of OPA GMTs in subjects 18-49 years of age and 60-64 years of age. (See Table 16.)
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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. For 12 serotypes, immune responses were related to age, with adults aged 18-49 years showing statistically significantly greater responses than adults aged 60-64 years. Similarly, statistically significantly greater responses for 12 serotypes were observed for adults in age subgroups 18-29 years, 30-39 years and 40-49 years compared with adults aged 60-64 years. OPA GMTs were highest in adults aged 18-29 years and lowest in adults aged 60-64 years.
One (1) year after vaccination with Prevenar 13, OPA titers had declined compared to titers measured 1 month after vaccination ranging from 23 to 2948; however, OPA titers for all serotypes remained higher than levels measured at baseline ranging from 5 to 186.
Immune responses in special populations: Individuals with the conditions described as follows have an increased risk of pneumococcal disease.
Sickle cell disease: An open-label single-arm study (6096A1-3014 [B1851013]) with 2 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 1 or more doses of PPSV23 at least 6 months prior to enrollment. After the first vaccination, Prevenar 13 elicited antibody levels measured by both IgG GMCs and OPA GMTs that were statistically significant higher when compared to levels prior to vaccination. After the second dose immune responses were comparable to the ones after the first dose. One (1) year after the second dose, antibody levels measured by both IgG GMCs and OPA GMTs were higher than levels prior to the first dose of Prevenar 13, except the IgG GMC for serotype 3 that was similar.
Additional pneumococcal 7-valent conjugate vaccine immunogenicity data: children with sickle cell disease: The immunogenicity of pneumococcal 7-valent conjugate vaccine has been investigated in an open-label, multicenter study (0887X1-100722) in 49 infants with sickle cell disease. Children were vaccinated with pneumococcal 7-valent conjugate vaccine (3 doses 1 month apart from the age of 2 months), and 46 of these children also received a PPSV23 at the age of 15-18 months. After primary immunisation, 95.6% of the subjects had antibody levels of >0.35 μg/mL for all 7 serotypes found in pneumococcal 7-valent conjugate vaccine. A significant increase was seen in the concentrations of antibodies against the 7 serotypes after PPSV23, suggesting that immunological memory was well established.
HIV infection:
Children and adults not previously vaccinated with a pneumococcal vaccine: In study 6115A1-3002 (B1851021), HIV-infected children and adults (CD4 ≥200 cells/µL, viral load <50,000 copies/mL and free of active AIDS-related illness) not previously vaccinated with a pneumococcal vaccine received 3 doses of Prevenar 13. As per general recommendations, a single dose of PPSV23 was subsequently administered. Vaccines were administered at 1 month intervals. Immune responses were assessed in 259-270 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 were statistically significantly higher when compared to levels prior to vaccination. After the second and third 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: In study 6115A1-3017 (B1851028), immune responses were assessed in 329 HIV-infected adults ≥18 years of age (CD4+ T-cell count ≥200 cells/µL and viral load <50,000 copies/mL) previously vaccinated with PPSV23 administered at least 6 months prior to enrollment. Subjects received 3 doses of Prevenar 13, at enrollment, 6 months and 12 months after the first dose of Prevenar 13. After the first vaccination, Prevenar 13 elicited antibody levels measured by both IgG GMCs and OPA GMTs that were statistically significant higher 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. Subjects who received two or more previous doses of PPSV23 showed a similar immune response compared with subjects who received a single previous dose.
Hematopoietic stem cell transplant:
In study 6115A1-3003 (B1851022), children and adults with an allogeneic HSCT at ≥2 years of age received 3 doses of Prevenar 13 with an interval of at least 1 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 general recommendations, a single dose of PPSV23 was administered 1 month after the fourth dose of Prevenar 13. Immune responses as measured by IgG GMCs were assessed in 168-211 evaluable subjects approximately 1 month after vaccination. Prevenar 13 elicited increased 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.
Clinical trials conducted in adults previously vaccinated with PPSV23 (pre-vaccinated):
In a Phase 3 active-controlled, modified
2 double-blind clinical trial (6115A1-3005) of Prevenar 13 in the US and Sweden, PPSV23 pre-vaccinated adults aged ≥70 years who had received 1 dose of PPSV23 ≥5 years prior were randomly assigned (1:1) to receive either Prevenar 13 or PPSV23.
The OPA antibody responses elicited by Prevenar 13 were non-inferior for the 12 serotypes in common to those elicited by PPSV23 when the vaccines were administered at a minimum of 5 years after PPSV23. In addition, 10 of the serotypes in common exhibited a statistically significantly greater immune response after Prevenar 13 compared with after PPSV23.
For serotype 6A, which is unique to Prevenar 13, proportions of adults with a 4-fold increase after Prevenar 13 (71.1%) was significantly greater than after PPSV23 (27.3%) in PPSV23-pre-vaccinated adults aged ≥70 years. OPA GMTs for serotype 6A were statistically significantly greater after Prevenar 13 compared with after PPSV23.
2Modified double-blind means that the site staff dispensing and administering the vaccine were unblinded, but all other study personnel including the principal investigator and subject were blinded.
This clinical trial demonstrated that in adults aged ≥70 years and pre-vaccinated with PPSV23 ≥5 years prior, vaccination with Prevenar 13 shows an improved immune response as compared to re-vaccination with PPSV23. (See Table 17.)
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Clinical trials to assess Prevenar 13 given with seasonal TIV in adults: Two (2) randomized, double-blind clinical trials (6115A1-3001 and 6115A1-3008) evaluated the immunogenicity of Prevenar 13 given with TIV (A/H1N1, A/H3N2, and B strains) in adults who were PPSV23 unvaccinated aged 50-59 years and in adults ≥65 years.
Each clinical trial compared concomitant administration of Prevenar 13 and TIV (administered in opposite arms) with [1] TIV given with placebo and [2] with Prevenar 13 given alone. Group 1 received Prevenar 13 given with TIV, followed 1 month later by placebo; Group 2 received TIV given with placebo, followed 1 month later by Prevenar 13.
A Phase 3 randomized, double-blind clinical trial (6115A1-3001) of Prevenar 13 given with TIV in adults aged 50-59 years who were PPSV23 unvaccinated in the US assessed the immune responses of TIV when TIV was given with Prevenar 13 compared with TIV given with placebo (in the following called TIV alone).
A Phase 3 randomized, double-blind clinical trial (6115A1-3008) of Prevenar 13 given with TIV to adults aged ≥65 years who were PPSV23 unvaccinated in Europe assessed the immune responses of TIV when TIV was given with Prevenar 13 compared with TIV given with placebo.
Immune responses elicited by TIV were measured by haemagglutination inhibition (HAI) assays 1 month after TIV vaccination. The immune responses were measured as the proportion of adults achieving a ≥4-fold increase in HAI titer (responder) for each TIV strain 1 month after vaccination. The non-inferiority criterion was achieved for each vaccine antigen if the lower limit of the 95% CI for the difference in proportions of responders was >-10%.
The studies also assessed the immune responses of Prevenar 13 when Prevenar 13 was given with TIV compared with Prevenar 13 given alone. The immune responses elicited by Prevenar 13 were measured by ELISA IgG GMC 1 month after Prevenar 13 vaccination. The non-inferiority criterion was achieved if the lower limit of the 2-sided, 95% CI for the IgG GMC ratios (Prevenar 13 and TIV relative to Prevenar 13 alone) was >0.5 (2-fold criterion).
TIV immune responses 50-59 years of age: The immune responses were similar after Prevenar 13 given concomitantly with TIV compared to TIV alone. Non-inferiority was met for all 3 TIV strains after Prevenar 13 given concomitantly with TIV compared to TIV alone (Table 18).
TIV immune responses in ≥65 years of age: The immune responses were similar after Prevenar 13 given concomitantly with TIV compared to TIV alone. Non-inferiority was met for A/H1N1, and B-strains but not for A/H3N2 with a lower limit of the 95% CI of -10.4% (Table 19). (See Tables 18 and 19.)
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Prevenar 13 immune responses in 50-59 years old: Non-inferiority was met for all serotypes (Table 20). (See Table 20.)
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Prevenar 13 immune responses in ≥65 years old: Non-inferiority was met for all serotypes except serotype 19F. The lower limit of the 95% CI of the GMR for 19F was 0.49 [criterion 0.5] (Table 21). (See Table 21.)
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Prevenar 13 may be administered concomitantly with seasonal TIV.
When Prevenar 13 was given concomitantly with TIV, the immune responses to TIV were similar to the responses when TIV was given alone.
When Prevenar 13 was given concomitantly with TIV, the immune responses to Prevenar 13 were lower compared to when Prevenar 13 was given alone. The clinical significance of this is unknown.
Clinical trial to assess Prevenar 13 given with seasonal QIV in adults:
A randomized, double-blind post-marketing study evaluated the immunogenicity of Prevenar 13 given with inactivated QIV (Fall 2014/Spring 2015 Fluzone, A/H1N1, A/H3N2, B/Brisbane, and B/Massachusetts strains) in PPSV23 previously vaccinated adults aged ≥50 years conducted in the US. One group received Prevenar 13 and QIV concurrently, followed approximately 1 month later by placebo. The other group received QIV and placebo concurrently, followed approximately 1 month later by Prevenar 13.
The antibody responses elicited by Prevenar 13 were measured as OPA GMTs 1 month after Prevenar 13 vaccination. Non-inferiority was demonstrated if the lower limit of the 2-sided 95% CI for the OPA GMT ratios (Prevenar 13 + QIV relative to Prevenar 13 alone) was >0.5. Prevenar 13 mcOPA antibody responses met non-inferiority for all 13 serotypes after Prevenar 13 was given concomitantly with QIV compared to Prevenar 13 given alone (Table 22). (See Table 22.)
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Antibody responses elicited by QIV were measured by HAI 1 month after QIV vaccination. The immune responses were measured as HAI GMTs for each QIV strain 1 month after vaccination. Non-inferiority was demonstrated for each vaccine antigen if the lower limit of the 2-sided 95% CI for the GMT ratio of the HAI titer was >0.5. Non-inferiority was demonstrated for each of the 4 QIV strains after Prevenar 13 was given concomitantly with QIV compared with QIV given alone (Table 23). (See Table 23.)
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Pharmacokinetics: Evaluation of pharmacokinetic properties is not available for vaccines.
Toxicology: Preclinical safety data: A repeated-dose intramuscular (5 IM doses) rabbit toxicity study of Prevenar 13 resulted in the generation of serotype-specific antibody responses and did not demonstrate any significant local or systemic adverse effects. In addition, there were no significant adverse findings in a single-dose IM local tolerance study in rabbits.
In single-dose subcutaneous (SC) safety pharmacology studies of Prevenar 13 in rats or monkeys, there were no effects on central nervous, respiratory, or cardiovascular systems. In repeated-dose (7 SC doses) toxicity studies in rats and monkeys, no significant adverse effects were observed. In addition, in a repeated-dose (5 SC doses) toxicity study in juvenile rats, no significant adverse effects were observed.
A reproductive toxicity study in female rabbits showed that IM administration of Prevenar 13 prior to mating and during gestation did not affect fertility, embryo/fetal development, or post-natal development.
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