Prevnar 13

Prevnar 13 Mechanism of Action

vaccine, pneumococcal

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Action
Pharmacotherapeutic Group: Pneumococcal vaccines. ATC Code: J07AL02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Prevnar 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 CRM197 carrier protein. 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 immunoglobulin G (IgG) component] and memory B-cells that rapidly mobilize and secrete antibodies upon re-exposure to the same antigen.
Bacterial capsular polysaccharides (PS) are T-cell-independent antigens that stimulate mature B-lymphocytes, but not T-lymphocytes. In the absence of T-lymphocyte help, PS-stimulated B-cells predominantly produce immunoglobulin M (IgM) antibodies, have no affinity maturation or generation of memory B-cells (anamnestic or booster response). Polysaccharide vaccines are associated with poor or absent immunogenicity in infants <24 months and failure to induce immunological memory at any age. Conjugation of a PS to a protein carrier changes the nature of the antibody response from T-cell-independent to T-cell-dependent. Such protein carrier-specific T-lymphocytes provide the signals needed for maturation of the B-cell response and generation of B-cell memory, allowing an anamnestic (booster) response on re-exposure to pneumococcal polysaccharides.
Based on serotype surveillance in Europe performed before the introduction of pneumococcal 7-valent conjugate vaccine, Prevnar 13 is estimated to cover 83-93% (depending on the country) of serotypes causing invasive pneumococcal disease (IPD) among infants and young children.
Prevnar 13 is estimated to cover over 90% of serotypes causing antibiotic-resistant IPD.
Clinical Trials Data on Efficacy: Disease Burden for Infants and Children: Streptococcus pneumoniae is an important cause of morbidity and mortality in persons of all ages worldwide. The organism causes invasive infections eg, bacteremia and meningitis, as well as pneumonia and upper respiratory tract infections, including otitis media and sinusitis. In children >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. In the US, the serotypes causing the majority of disease in the 1990s were the basis for the development of the pneumococcal 7-valent conjugate vaccine and included serotypes 4, 6B, 9V, 14, 18C, 19F and 23F.
Prior to the introduction of the pneumococcal 7-valent conjugate vaccine, the incidence of IPD among children <2 years 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 noninvasive pneumonia, even among children. Prior to the licensure of the pneumococcal 7-valent conjugate vaccine, the estimated incidence of pneumonia among children <2 years 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 pneumococcal 7-valent conjugate vaccine was licensed in the US for infants and children in 2000, following a randomized, double-blinded clinical trial in a multiethnic population at Northern California Kaiser Permanente (NCKP) from October 1995 through August 20, 1998, in which 37,816 infants were randomized to receive either the pneumococcal 7-valent conjugate vaccine or a control vaccine [an investigational meningococcal group C conjugate vaccine (MnCC)] at 2, 4, 6 and 12-15 months. In this study, the efficacy of the pneumococcal 7-valent conjugate vaccine against invasive disease due to S. pneumoniae in cases accrued during this period was 100% in both the per-protocol and intent-to-treat analyses (95% CI, 75.4-100% and 81.7-100%, respectively). Data accumulated through an extended follow-up period to April 20, 1999, resulted in similar efficacy estimates of 97.3% in the per-protocol analysis and 94.4% in the intent-to-treat analysis. Since the vaccine's introduction, a 98% reduction in IPD caused by vaccine serotypes has been observed among children <5 years through 2005, attesting to the high effectiveness of the pneumococcal 7-valent conjugate vaccine in routine use. While the effect of routine use of the pneumococcal 7-valent conjugate vaccine in infants and young children has been dramatic, with a near-total elimination of the serotypes contained in this vaccine, a proportional increase in other serotypes causing IPD has been observed (as an increasing percentage of residual disease). Specifically, while serotype 19A was the 9th most commonly isolated serotype causing IPD in the US prior to the introduction of the pneumococcal 7-valent conjugate vaccine, according to both centers for disease control (CDC) and independent surveillance, as of 2005, serotype 19A had become the predominant pneumococcal serotype causing IPD in US children, accounting for approximately 30-45% of the residual IPD in 2005 in children <5 years. Compounding the issue of the predominance of emerging serotype 19A is that it is increasingly likely to be nonsusceptible to commonly used 1st-line antimicrobial agents. Furthermore, approximately 66% of the serotyped IPD cases occurring in children <5 years in 2006-2007 in the CDC and prevention active bacterial core surveillance were due to serotypes 1, 19A, 7F, 3, 6A and 5 included in Prevnar 13. In various recent US surveys conducted by other investigators, >45% and up to 60% of residual IPD cases in pediatric subjects were caused by these 6 additional serotypes.
Epidemiologic observations in the US since the introduction of the pneumococcal 7-valent conjugate vaccine have shown that not only has invasive disease been significantly reduced among vaccinated children, especially that caused by serotypes included in the vaccine, but it has also been reduced both among persons >5 years (a population for whom the conjugate vaccine is not routinely recommended) and among infants too young to be eligible for immunization. It is generally believed that the reduction in disease among unvaccinated people is the result of herd immunity or indirect effect, a phenomenon that occurs via interruption of transmission of disease to otherwise susceptible populations, resulting in an observed reduction in disease overall. In this case, herd immunity is observed in unvaccinated populations due to the ability of the pneumococcal 7-valent conjugate vaccine to interrupt transmission of pneumococci from vaccinated children to their unvaccinated contacts. It is expected that there will be similar population responses related to Prevnar 13 when used routinely.
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 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. In particular, reviews of hospital utilization databases in the US found a 39-52.4% reduction in hospitalizations for all-cause pneumonia and a 57.6-65% reduction in hospitalizations coded as pneumococcal pneumonia, in children <2 years. While uncomplicated pneumonia is generally considered noninvasive disease, pneumococcal pneumonia may be complicated by both bacteremia and locally invasive manifestations, including pleural empyema and pulmonary necrosis. Observations in the US since the introduction of the pneumococcal 7-valent conjugate vaccine suggest that complicated, invasive pneumonia may be increasing, and that these more severe manifestations of pneumonia are more likely to be associated with serotypes included in Prevnar 13 (1, 3, 19A and 7F); serotype 3 in particular has been associated with necrotizing pneumonia.
Streptococcus pneumoniae is also a major cause of noninvasive disease in children, particularly of acute otitis media (AOM). Acute otitis media is a common childhood disease, with >60% of children experiencing an episode by 1 year and >90% of children experiencing an episode by age 5. Prior to the US introduction of the pneumococcal 7-valent conjugate vaccine in the year 2000, approximately 24.5 million ambulatory care visits and 490,000 procedures for myringotomy with tube placement were attributed to otitis media annually. The peak incidence of AOM is 6-18 months. Otitis media is less common, but occurs, in older children. In a 1990 surveillance report by the CDC, otitis media was the most common principal illness diagnosis in children 2-10 years. 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 eg, mastoiditis and meningitis. Streptococcus 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 nontypeable Haemophilus influenzae or Moraxella catarrhalis.
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 1662 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. 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. 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 nonsignificant 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.
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.
Disease Burden for Adults: Streptococcus 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 600,000-800,000 are adults. Pneumococcal disease can be classified by the degree of bacterial invasion, which is predictive of complications and mortality. Invasive pneumococcal disease is defined by the isolation of pneumococcus from a normally sterile site eg, 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.
Adults >50 years, especially those >65 years, 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 eg, ≥18 years. 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. Among hospitalized patients in the United States, the all-case fatality rate from IPD remains high (12-16%) and is much higher in many subgroups including those with increased age, comorbidities, complications of IPD and admission to intensive care units. Despite advances in medical science over the last decades, there has been little change in mortality rates since penicillin's introduction.
The reported incidence of IPD worldwide ranges from 45-90/100,000. Prior to the introduction of pneumococcal 7-valent conjugate vaccine into National Immunization Programs (NIP), the IPD incidence for Canadian adults ≥65 years ranged from 16-31/100,000, while for US residents of the same age, the IPD incidence ranged from 60-65/100,000 (with rates of 190/100,000 documented among members of the Navajo Nation). The IPD incidence for older Europeans in the same age group ranged from 41 in Sweden to 66/100,000 in Denmark, with a particularly high rate documented in the older age groups beyond 65 years, for instance, in the Netherlands or the UK. In the United States, a decrease in adult disease after the initiation of childhood vaccination has been noted, presumably due to reduction of pneumococcal colonization in infants and spread to susceptible adults (herd protection). However, the incidence of IPD in adults, especially the elderly, has remained high ranging from 23/100,000-29.4/100,000. Although the incidence estimates among adults younger than 65 are lower than those among adults older than 65, IPD represents a major public health burden among younger adults as well.
Pneumonia is one of the most common infectious diseases. In the United States, during 2006, over 4 million cases of pneumonia due to all causes were reported in adults. Rates of hospitalized CAP in Europe range from 200-260/100,000, with 75% of CAP cases being managed in the community. Higher rates of CAP have been noted in the developing world, within specific genetic groups, in populations with lower socioeconomic status and in groups with less access to healthcare. 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. However, the incidence of non-bacteremic pneumonia caused by S. pneumoniae is more difficult to ascertain, because the causative pathogen is not identified in the majority of cases despite aggressive efforts. Yet, S. pneumoniae is still the leading cause of community-acquired pneumonia accounting for 25-35% of all cases requiring hospitalization and resulting in an overall case fatality rate of 12%.
While host factors eg, age and comorbid conditions contribute to the likelihood of IPD and poor outcomes, there has been increasing appreciation that pathogen virulence and antibiotic resistance play an important role. Although >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 antibiotic resistance.
Antibiotic 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 antibiotic resistance, serotypes 6A, 6B, 9V, 14, 15A, 19F, 19A and 23F were most likely to demonstrate resistance to both penicillin and erythromycin.
Prevnar 13 provides an immune response against prevalent strains of S. pneumoniae including those most likely to cause disease, be antibiotic resistant, and result in poor outcomes. (See Table 1.)

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Prevnar 13 Immunogenicity Clinical Studies in Infants and Children: The World Health Organization (WHO) has recommended a serum anti-capsular polysaccharide antibody concentration of 0.35 mcg/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 CRM197 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. The percentage of infants achieving pneumococcal anti-capsular polysaccharide IgG antibody concentrations ≥0.35 mcg/mL 1 month after a 3-dose primary series in representative studies are presented as follows (see Table 2):

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In Prevnar 13 recipients, antipolysaccharide 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 Prevnar 13 was noninferior to that of pneumococcal 7-valent conjugate vaccine for all 13 serotypes using a set of predefined immunological noninferiority criteria. Immune responses elicited by Prevnar 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 Primary Series: The immunogenicity after 2 doses in infants has been documented in 4 studies. The proportion of infants achieving a pneumococcal anticapsular polysaccharide IgG concentration ≥0.35 mcg/mL 1 month after the 2nd dose ranged from 79.6-98.5% across 11 of the 13 vaccine serotypes. Smaller proportions of infants achieved this antibody concentration threshold for serotype 6B (27.9-58.4%) and 23F (55.8-68.6%). Compared to a 3-dose infant series, pneumococcal anti-capsular polysaccharide IgG geometric mean concentration (GMC) 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 Series: Post-booster antibody concentrations were higher for 12 serotypes than those achieved after the infant primary series, which is consistent with adequate priming (the induction of immunologic memory). For serotype 3, antibody concentrations following the infant primary series and booster dose were similar. Antibody responses to booster doses following 2-dose or 3-dose infant primary series were comparable for all 13 vaccine serotypes.
For children 7 months to 5 years, age appropriate catch-up immunization schedules (as described in Dosage & Administration) result in levels of anticapsular 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.
Booster Responses to Prevnar 13 Following a 3-Dose Primary Infant Series of Pneumococcal 7-Valent Conjugate Vaccine or Prevnar 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: Prevnar 13 at 2, 3, 4 and 12 months or; pneumococcal 7-valent conjugate vaccine at 2, 3 and 4 months followed by Prevnar 13 at 12 months or; pneumococcal 7-valent conjugate vaccine at 2, 3, 4 and 12 months. Geometric mean concentrations of anticapsular polysaccharide IgG antibody responses to each of the 13 serotypes in the 3 groups are shown in Table 3 (see Table 3). Geometric mean concentration 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/Prevnar 13 recipients were lower than those observed with the 4-dose Prevnar 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 3.)

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Preterm Infants [B1851037 (6096A1-4001)]: Safety and immunogenicity of Prevnar 13 given at 2, 3, 4 and 12 months was assessed in 100 prematurely born infants [estimated gestational age (EGA) mean, 31 weeks; range, 26-36 weeks] and compared with 100 infants born at term (EGA mean, 39 weeks; range, 37-42 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 mcg/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 (1) 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.
Previously Unvaccinated Older Infants and Children: In an open-label study of Prevnar 13 in Poland (6096A1-3002), children 7-11 months, 12-23 months and ≥24 months to 5 years (prior to the 6th birthday) who were naive to pneumococcal conjugate vaccine, were given 3, 2 or 1 dose of Prevnar 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 4 (see Table 4).
These age appropriate catch-up immunization schedules result in levels of anticapsular 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 4.)

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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 Prevnar 13. Immune responses to selected concomitant vaccine antigens were compared in infants receiving pneumococcal 7-valent conjugate vaccine and Prevnar 13. The proportion of responders at prespecified antibody levels is shown in Table 5 (see Table 5). Responses to all antigens in Prevnar 13 recipients were similar to those in pneumococcal 7-valent conjugate vaccine recipients and met formal criteria for noninferiority. Varicella responses as measured by a commercial whole cell enzyme-linked immunosorbent assay (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 Prevnar 13. (See Table 5.)

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Children and Adolescents 5-17 Years: In study 6096A1-3011 in the US, in children 5 to <10 years previously vaccinated with at least 1 dose of pneumococcal 7-valent conjugate vaccine, and in pneumococcal vaccine-naive children and adolescents 10-17 years, 1 dose of Prevnar 13 elicited immune responses to all 13 serotypes.
In children 5 to <10 years, serum IgG concentrations for the 7 common serotypes 1 month after administration of a single dose of Prevnar 13 vaccination (study 6096A1-3011) were noninferior [ie, the lower limit of the 2-sided 95% CI for the geometric mean ratio (GMR) of >0.5] to those elicited by the 4th dose of pneumococcal 7-valent conjugate vaccine at 12-15 months (study 6096A1-3005). In addition, IgG concentrations elicited by a single dose of Prevnar 13 for the 6 additional serotypes in children 5 to <10 years were noninferior to those elicited by the 4th dose of Prevnar 13 at 12-15 months (study 6096A1-3005) as shown in Tables 6 and 7. (See Tables 6 and 7.)

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In children and adolescents 10-17 years, opsonophagocytic activity (OPA) GMTs 1 month after vaccination were noninferior (ie, 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 8. (See Table 8.)

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Prevnar 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 Prevnar 13. Prevnar 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 Prevnar 13 or pneumococcal 7-valent conjugate vaccine at 2, 4, 6 and 12 months in Israel. Prevnar 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.
Prevnar 13 Immunogenicity Clinical Trials in Adults: An antipolysaccharide-binding antibody IgG level to predict protection against IPD or non-bacteremic pneumonia has not been defined for adults. However, nonclinical and clinical data support functional antibody, measured by OPA assay, as a contributor to protection against pneumococcal disease. Opsonophagocytic activity 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. Opsonophagocytic activity titers are expressed as the reciprocal of the highest serum dilution that reduces survival of the pneumococci by at least 50%. Pivotal trials for Prevnar 13 were designed to show that functional OPA antibody responses for the Prevnar 13 serotypes are noninferior and for some serotypes, superior to the common serotypes in the currently licensed PPSV23.
Serotype-specific OPA GMTs measured 1 month after each vaccination were calculated. Noninferiority 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 Prevnar 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 Prevnar 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 >0. 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 Prevnar 13 in different age groups, and in individuals who were either not previously vaccinated (PPSV23 unvaccinated) with PPSV23 or had received ≥1 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 noninferiority trials were conducted in which Prevnar 13 response was compared to PPSV23 immune response, 1 in PPSV23 unvaccinated adults 50-64 years (6115A1-004), and 1 in PPSV23 pre-vaccinated adults ≥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 Prevnar 13 with seasonal trivalent inactivated influenza vaccine (TIV).
Clinical Trials Conducted in Adults Not Previously Vaccinated with PPSV23: In an active-controlled modified double-blind (the site-staff dispensing and administering the vaccine were unblinded, but all other study personnel including the principal investigator and subject were blinded) clinical trial (6115A1-004) of Prevnar 13 in the US, PPSV23-unvaccinated adults 60-64 years were randomly assigned (1:1) to receive Prevnar 13 or PPSV23. In addition, adults 18-49 years (with age subgroups 18-29 years, 30-39 years, 40-49 years) and 50-59 years were enrolled and received 1 dose of Prevnar 13 (open-label).
The OPA antibody responses elicited by Prevnar 13 were noninferior 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 Prevnar 13 compared with after PPSV23.
For serotype 6A, which is unique to Prevnar 13, the proportions of adults with a 4-fold increase after Prevnar 13 (88.5%) were significantly greater than after PPSV23 (39.2%) in PPSV23-unvaccinated adults 60-64 years. Opsonophagocytic activity GMTs for serotype 6A were statistically significantly greater after Prevnar 13 compared with after PPSV23.
The OPA responses elicited by Prevnar 13 in adults 50-59 years were noninferior to the Prevnar 13 responses in adults 60-64 years for all 13 serotypes. In addition, 9 of the 13 serotypes exhibited a statistically significantly greater immune response in adults 50-59 years compared with adults 60-64 years.
This clinical trial demonstrated that the immune responses elicited by Prevnar 13 are noninferior and for most serotypes statistically significantly greater than PPSV23. In addition, the immune responses in adults 50-59 years were noninferior and for most serotypes statistically significantly greater than those observed in adults 60-64 years.
In adults 60-64 years, antibody levels 1 year after vaccination were greater after Prevnar 13 compared to antibody levels after PPSV23 for 7 of 12 serotypes in common. In adults 50-59 years, antibody levels 1 year after vaccination with Prevnar 13 were greater for 12 of 13 serotypes compared to vaccination with Prevnar 13 in 60-64 year olds. (See Table 9.)

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Table 10 shows OPA GMTs 1 month after vaccination in subjects 18-29, 30-39 and 40-49 years given a single dose of Prevnar 13. It also shows a comparison of OPA GMTs in subjects 18-49 years and 60-64 years. (See Table 10.)

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In adults 18-29 years, OPA GMTs to all 13 serotypes in Prevnar 13 were noninferior to the Prevnar 13 responses in adults 60-64 years. For 12 serotypes, immune responses were related to age, with adults 18-49 years showing statistically significantly greater responses than adults 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 60-64 years. Opsonophagocytic activity GMTs were highest in adults 18-29 years and lowest in adults 60-64 years.
One (1) year after vaccination with Prevnar 13 OPA titers had declined compared to titers measured 1 month after vaccination ranging from 23-2948; however, OPA titers for all serotypes remained higher than levels measured at baseline ranging from 5-186.
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 Prevnar 13 given 6 months apart was conducted in 158 children and adolescents ≥6 to <18 years with sickle cell disease who were previously vaccinated with ≥1 doses of PPSV23 at least 6 months prior to enrollment. After the 1st vaccination, Prevnar 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 2nd dose, immune responses were comparable to the ones after the 1st dose. One (1) year after the 2nd dose, antibody levels measured by both IgG GMCs and OPA GMTs were higher than levels prior to the 1st dose of Prevnar 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 immunization, 95.6% of the subjects had antibody levels of >0.35 mcg/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.
Adults with 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/microL, viral load <50,000 copies/mL and free of active AIDS-related illness) not previously vaccinated with a pneumococcal vaccine received 3 doses of Prevnar 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 1st dose, Prevnar 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 2nd and 3rd dose of Prevnar 13, immune responses were similar or higher than those after the 1st 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 (CD4+ T-cell count >200 cells/microL and viral load <50,000 copies/mL) previously vaccinated with PPSV23 administered at least 6 months prior to enrollment. Subjects received 3 doses of Prevnar 13, at enrollment, 6 months and 12 months after the 1st dose of Prevnar 13. After the 1st vaccination, Prevnar 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 2nd and 3rd dose of Prevnar 13, immune responses were comparable or higher than those after the 1st dose. Subjects who received ≥2 previous doses of PPSV23 showed a similar immune response compared with subjects who received a single previous dose.
Hematopoietic Stem Cell Transplant (HSCT): In study 6115A1-3003 (B1851022), children and adults with an allogeneic HSCT at ≥2 years received 3 doses of Prevnar 13 with an interval of at least 1 month between doses. The 1st dose was administered at 3-6 months after HSCT. A 4th (booster) dose of Prevnar 13 was administered 6 months after the 3rd dose. As per general recommendations, a single dose of PPSV23 was administered 1 month after the 4th dose of Prevnar 13. Immune responses as measured by IgG GMCs were assessed in 168-211 evaluable subjects approximately 1 month after vaccination. Prevnar 13 elicited increased antibody levels after each dose of Prevnar 13. Immune responses after the 4th dose of Prevnar 13 were significantly increased for all serotypes compared with after the 3rd dose.
This study demonstrated that 4 doses of Prevnar 13 elicited serum IgG concentrations similar to those induced by a single dose in healthy individuals of the same age group.
Clinical Trials Conducted in Adults Previously Vaccinated with PPSV23 (Pre-Vaccinated): In a phase 3 active-controlled, modified double-blind (the site-staff dispensing and administering the vaccine were unblinded, but all other study personnel including the principal investigator and subject were blinded) clinical trial (6115A1-3005) of Prevnar 13 in the US and Sweden PPSV23-pre-vaccinated adults ≥70 years who had received 1 dose of PPSV23 ≥5 years prior were randomly assigned (1:1) to receive either Prevnar 13 or PPSV23.
The OPA antibody responses elicited by Prevnar 13 were noninferior 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 Prevnar 13 compared with after PPSV23.
For serotype 6A, which is unique to Prevnar 13, proportions of adults with a 4-fold increase after Prevnar 13 (71.1%) was significantly greater than after PPSV23 (27.3%) in PPSV23-pre-vaccinated adults ≥70 years. Opsonophagocytic activity GMTs for serotype 6A were statistically significantly greater after Prevnar 13 compared with after PPSV23.
This clinical trial demonstrated that in adults ≥70 years and pre-vaccinated with PPSV23 ≥5 years prior, vaccination with Prevnar 13 shows an improved immune response as compared to re-vaccination with PPSV23. (See Table 11.)

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Clinical Trials to Assess Prevnar 13 Given With Seasonal Trivalent Inactivated Influenza Vaccine (TIV) in Adults: Two (2) randomized, double-blind clinical trials (6115A1-3001 and 6115A1-3008) evaluated the immunogenicity of Prevnar 13 given with TIV (A/H1N1, A/H3N2 and B strains) in adults who were PPSV23 unvaccinated 50-59 years and in adults ≥65 years.
Each clinical trial compared concomitant administration of Prevnar 13 and TIV (administered in opposite arms) with TIV given with placebo and with Prevnar 13 given alone. Group 1 received Prevnar 13 given with TIV, followed 1 month later by placebo; group 2 received TIV given with placebo, followed 1 month later by Prevnar 13.
A phase 3 randomized, double-blind clinical trial (6115A1-3001) of Prevnar 13 given with TIV in adults 50-59 years who were PPSV23 unvaccinated in the US assessed the immune responses of TIV when TIV was given with Prevnar 13 compared with TIV given with placebo (in the following called TIV alone).
A phase 3 randomized, double-blind clinical trial (6115A1-3008) of Prevnar 13 given with TIV in adults ≥65 years who were PPSV23 unvaccinated in Europe assessed the immune responses of TIV when TIV was given with Prevnar 13 compared with TIV given with placebo.
Immune responses elicited by TIV were measured by hemagglutination 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 noninferiority 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 Prevnar 13 when it was given with TIV compared with Prevnar 13 given alone. The immune responses elicited by Prevnar 13 were measured by ELISA IgG GMC 1 month after Prevnar 13 vaccination. The noninferiority criterion was achieved if the lower limit of the 2-sided, 95% CI for the IgG GMC ratios (Prevnar 13 and TIV relative to Prevnar 13 alone) was >0.5 (2-fold criterion).
Trivalent Inactivated Influenza Vaccine Immune Responses 50-59 Years: The immune responses were similar after Prevnar 13 given concomitantly with TIV compared to TIV alone. Noninferiority was met for all 3 TIV strains after Prevnar 13 given concomitantly with TIV compared to TIV alone (see Table 12).
Trivalent Inactivated Influenza Vaccine Immune Responses in ≥65 Years: The immune responses were similar after Prevnar 13 given concomitantly with TIV compared to TIV alone. Noninferiority was met for A/H1N1, and B-strains but not for A/H3N2 with a lower limit of the 95% CI of -10.4% (see Table 13). (See Tables 12 and 13.)

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Prevnar 13 Immune Responses in 50-59 Years: Noninferiority was met for all serotypes (see Table 14).
Prevnar 13 Immune Responses in ≥65 Years: Noninferiority 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) (see Tables 14 and 15).

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Prevnar 13 may be administered concomitantly with seasonal TIV. When Prevnar 13 was given concomitantly with TIV, the immune responses to TIV were similar to the responses when TIV was given alone. When Prevnar 13 was given concomitantly with TIV, the immune responses to Prevnar 13 were lower compared to when Prevnar 13 was given alone. The clinical significance of this is unknown.
Pharmacokinetics: Evaluation of pharmacokinetic properties is not available for vaccines.
Toxicology: Preclinical Safety Data: A repeated-dose IM (5 IM doses) rabbit toxicity study of Prevnar 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 SC safety pharmacology studies of Prevnar 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 Prevnar 13 prior to mating and during gestation did not affect fertility, embryo/fetal development or postnatal development.
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