PREVNAR 20™ Clinical Studies

14.1 Prevnar and Prevnar 13 Efficacy Data

Efficacy and effectiveness of Prevnar and Prevnar 13 are relevant to Prevnar 20, since Prevnar, Prevnar 13 and Prevnar 20 are manufactured similarly. In addition, Prevnar and Prevnar 20 contain 7 of the same polysaccharide conjugates and Prevnar 13 and Prevnar 20 contain 13 of the same polysaccharide conjugates.

Prevnar Efficacy Data in Children

Invasive Pneumococcal Disease (IPD)

Prevnar was licensed in the United States for infants and children in 2000, following a randomized, double‑blind, 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 Prevnar or a control vaccine (an investigational meningococcal group C conjugate vaccine [MnCC]) at 2, 4, 6, and 12 through 15 months of age. In this study, the efficacy of Prevnar against invasive disease due to S. pneumoniae in cases accrued during this period was 100% in both the per-protocol and intent-to-treat analyses (95% confidence interval [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 97.4% in the per-protocol analysis and 93.9% in the intent-to-treat analysis (95% CI: 82.7%, 99.9% and 79.6%, 98.5%, respectively).

Acute Otitis Media (AOM)

The efficacy of Prevnar against otitis media was assessed in 2 clinical trials: a trial in Finnish infants at the National Public Health Institute and the efficacy trial in US infants at NCKP.

The Finnish Otitis Media (FinOM) trial was a randomized, double-blind trial in which 1,662 infants were equally randomized to receive either Prevnar or a control vaccine Recombivax HB (Hepatitis B vaccine (Recombinant) [Hep B]) at 2, 4, 6, and 12 through 15 months of age. In this study, conducted between December 1995 and March 1999, parents of study participants were asked to bring their children to the study clinics if the child had respiratory infections or 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.

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, compared to children who received the control vaccine, suggesting that children who received Prevnar appeared to be at increased risk of otitis media due to pneumococcal serotypes not represented in the vaccine. However, vaccination with Prevnar 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.

In the NCKP trial, the efficacy of Prevnar against otitis media was assessed from the beginning of the trial in October 1995 through April 1998. The otitis media analysis included 34,146 infants randomized to receive either Prevnar (N=17,070), or the control vaccine (N=17,076), at 2, 4, 6, and 12 through 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. 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 Prevnar group and 18,941 in MnCC control group), resulted in similar otitis media efficacy estimates for all endpoints.

Prevnar 13 Adult Efficacy Data

The efficacy of Prevnar 13 against vaccine-type (VT) pneumococcal community-acquired pneumonia (CAP) and IPD was assessed in a randomized, double-blind, placebo-controlled study (Community-Acquired Pneumonia Immunization Trial in Adults [CAPiTA]) conducted over ~4 years in the Netherlands. A total of 84,496 participants 65 years of age and older received a single dose of either Prevnar 13 or placebo in a 1:1 randomization; 42,240 participants were vaccinated with Prevnar 13 and 42,256 participants were vaccinated with placebo. Chronic medical conditions (asthma, diabetes, heart, liver, and/or lung diseases) were reported in 42.3% of study participants at baseline.

The primary objective was to demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of confirmed VT-CAP (defined as presence of ≥2 specified clinical criteria, chest X-ray consistent with CAP as determined by a central committee of radiologists, and positive VT-specific urinary antigen detection assay [UAD] or isolation of VT S. pneumoniae from blood or other sterile site). The secondary objectives were to demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of 1) confirmed nonbacteremic/noninvasive (NB/NI) VT-CAP (an episode of VT-CAP for which the blood culture result and any other sterile site culture results were negative for S. pneumoniae) and 2) VT-IPD (the presence of S. pneumoniae in a sterile site).

Surveillance for suspected pneumonia and IPD began immediately after vaccination and continued through identification of a prespecified number of cases. Participants who had a CAP or IPD episode with symptom onset less than 14 days after vaccination were excluded from all analyses.

The median duration of follow-up per participant was 3.93 years. Prevnar 13 demonstrated statistically significant vaccine efficacy (VE) in preventing first episodes of VT pneumococcal CAP, NB/NI VT pneumococcal CAP, and VT-IPD (see Table 8).

14.2 Prevnar 20 Clinical Trials in Individuals 6 Weeks Through 15 Months of Age

Immunogenicity of Prevnar 20 in Individuals 6 Weeks Through 15 Months of Age

Prevnar 20 effectiveness against invasive pneumococcal disease in individuals 6 weeks through 15 months of age was demonstrated based on comparisons of serotype-specific antibody responses at 1 month after Dose 3 and 1 month after Dose 4 of Prevnar 20 to the antibody responses after vaccination with Prevnar 13.

Antibody responses elicited by Prevnar 20 and Prevnar 13 in these age groups were measured using a serotype-specific multiplex direct-binding Luminex immunoassay (dLIA), designed to determine the concentration of serotype-specific polysaccharide-binding IgG antibodies, and OPA assays to measure serotype-specific functional OPA titers for the 20 pneumococcal serotypes of Prevnar 20. A serotype-specific IgG antibody concentration corresponding to ≥0.35 µg/mL using the World Health Organization (WHO) enzyme linked immunosorbent assay (ELISA) has been used as the threshold value for the clinical evaluation of pneumococcal conjugate vaccines when measured one month after Dose 3 of the 4-dose immunization series. The dLIA, used to measure the IgG antibody concentration, was bridged to the WHO ELISA to establish dLIA specific threshold values for each vaccine serotype that correspond to the established ≥0.35 µg/mL WHO ELISA threshold value.

In Study 8, a multicenter, randomized, active-controlled, double-blind trial, participants were randomized in a 1:1 ratio to receive Prevnar 20 (N=1004) or Prevnar 13 (N=993) in a 4-dose schedule; vaccine was administered at 2, 4, 6, and 12 through 15 months of age. Pediarix and Hiberix were administered concomitantly with each of the 3 infant doses. M-M-R II and VARIVAX were administered with the fourth dose [see Adverse Reactions (6.1) and Clinical Studies (14.3)].

Study 8 assessed serotype-specific IgG response rates, IgG geometric mean concentrations (GMCs) and OPA GMTs measured at one month after Dose 3 and one month after Dose 4 for all 20 serotypes contained in Prevnar 20. For each of the 13 matched serotypes, IgG response in the Prevnar 20 group were compared with the corresponding response in the Prevnar 13 group. For the 7 additional serotypes (serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F), IgG response in the Prevnar 20 group were compared with the lowest response among the 13 matched vaccine serotypes excluding serotype 3 in the Prevnar 13 group.

Pneumococcal IgG Antibody Responses Following 3 Doses of Prevnar 20

IgG antibody responses following Prevnar 20 were noninferior to those following Prevnar 13 for 8 of the 13 matched serotypes and 6 of the 7 additional serotypes, as assessed by the percentage of participants meeting the predefined serotype-specific IgG concentration one month after Dose 3, using a 10% noninferiority criterion (the lower bound of the 2-sided 95% CI for the difference in percentages [Prevnar 20 minus Prevnar 13] greater than -10%). Five of the 13 matched serotypes (serotypes 1, 3, 4, 9V and 23F) did not meet the pre-specified noninferiority criterion, as the lower bounds of the 2-sided 95% CIs for the difference in percentages (Prevnar 20 minus Prevnar 13) were -12.1%, -20.1%, -12.0%, -11.3%, and -11.4% respectively. One additional serotype (serotype 12F) also did not meet the NI criterion when compared to serotype 23F (the Prevnar 13 serotype with the lowest percentage excluding serotype 3) in the Prevnar 13 group, the lower bound of the 2-sided 95% CI for the difference in percentage (Prevnar 20 minus lowest Prevnar 13) was -41.6% (Table 9).

Additional IgG GMC data at one month after Dose 3 and OPA data at one month after Dose 3, presented in Tables 10 and 12 respectively, support the effectiveness of Prevnar 20 for each of the 6 serotypes that failed to meet the pre-specified non-inferiority criterion.

At 1 month after Dose 3, IgG GMCs in the Prevnar 20 group were noninferior to the corresponding IgG GMCs in the Prevnar 13 group for all 20 vaccine serotypes, including the 6 serotypes that missed the noninferiority criterion based on the percentage of participants meeting pre-defined IgG concentrations at one month after Dose 3. For each of the 13 matched serotypes, IgG GMCs in the Prevnar 20 group were noninferior to the corresponding IgG GMCs in the Prevnar 13 group. For each of the 7 additional serotypes, IgG GMCs in the Prevnar 20 group were noninferior to the IgG GMC for serotype 19A (the lowest result among the 13 matched vaccine serotypes excluding serotype 3) in the Prevnar 13 group (Table 10).

Pneumococcal IgG Antibody Responses Following 4 Doses of Prevnar 20

For each of the 13 matched serotypes, IgG GMCs in the Prevnar 20 group were noninferior to the corresponding IgG GMCs in the Prevnar 13 group. For each of the 7 additional serotypes, IgG GMCs in the Prevnar 20 group were noninferior to the IgG GMC for serotype 1 (the lowest result among the 13 matched vaccine serotypes excluding serotype 3) in the Prevnar 13 group (Table 11).

Opsonophagocytic Activity Responses After 3 and 4 doses of Prevnar 20

Serotype-specific OPA GMTs at 1 month after Dose 3 and 1 month after Dose 4 were descriptively evaluated in a subset of participants who had received Prevnar 20 and Prevnar 13 in Study 8 (Table 12). For serotypes 1, 3, 4, 9V, 23F and 12F, for which non-inferiority was not met 1 month after Dose 3 (for the percentage of participants meeting the pre-defined serotype-specific IgG concentration), OPA GMTs at 1 month after Dose 3 were numerically similar across groups for the 5 matched serotypes and an OPA antibody response was generated to additional serotype 12F.

14.3 Prevnar 20 Clinical Trials in Individuals 18 Years of Age and Older

Immunogenicity of Prevnar 20 in Pneumococcal Vaccine Naïve Individuals

Prevnar 20 effectiveness in adults against invasive pneumococcal disease caused by the 20 vaccine serotypes and against pneumonia caused by the 13 serotypes in Prevnar 13 was demonstrated based on comparative immunogenicity to US-licensed pneumococcal vaccines (Prevnar 13 and PPSV23). Study 1, conducted in the United States and Sweden, was designed to evaluate immunologic noninferiority of Prevnar 20 to Prevnar 13 (for the 13 original S. pneumoniae serotypes) and PPSV23 (for the 7 new S. pneumoniae serotypes) in pneumococcal vaccine naive individuals ≥60 years of age. Antibody responses elicited by Prevnar 20 and the control pneumococcal vaccines were measured by serotype-specific serum OPA assays for the 20 pneumococcal serotypes at 1-month post-vaccination. OPA assays were used to measure functional antibodies to S. pneumoniae.

Study 1 included healthy individuals and immunocompetent individuals with stable underlying conditions, including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease, and medical risk conditions and behaviors (e.g., smoking) that are known to increase the risk of serious pneumococcal pneumonia and IPD. A stable medical condition was defined as a medical condition not requiring significant change in therapy in the previous 6 weeks (i.e., change to new therapy category due to worsening disease) or any hospitalization for worsening disease within 12 weeks before receipt of the study vaccine.

Comparison of Immune Responses of Prevnar 20 to Prevnar 13 and PPSV23 in Pneumococcal Vaccine Naïve Individuals ≥60 Years of Age

In a randomized, active-controlled, double-blind noninferiority clinical trial (Study 1) of Prevnar 20 in the United States and Sweden, pneumococcal vaccine -naïve individuals 18 years of age and older were enrolled into 1 of 3 cohorts based on their age at enrollment and randomized to receive either Prevnar 20 or control. Participants 60 years of age and older were randomly assigned (1:1 ratio) to Prevnar 20 followed 1 month later with saline placebo or to Prevnar 13 followed 1 month later with PPSV23.

Serotype-specific OPA GMTs were measured before the first vaccination and 1 month after each vaccination. Noninferiority of immune responses, OPA GMTs 1 month after vaccination, with Prevnar 20 to a control vaccine for a serotype was declared if the lower bound of the 2 sided 95% CI for the GMT ratio (Prevnar 20/Prevnar 13; Prevnar 20/PPSV23) for that serotype was greater than 0.5.

In individuals 60 years of age and older, immune responses to all 13 matched serotypes elicited by Prevnar 20 were noninferior to the immune responses to the serotypes elicited by Prevnar 13 one month after vaccination. Immune responses to 6 out of the 7 additional serotypes induced by Prevnar 20 were noninferior to the immune responses to these same serotypes induced by PPSV23 one month after vaccination. The response to serotype 8 missed the prespecified statistical noninferiority criterion by a small margin (the lower bound of the 2-sided 95% CI for the GMT ratio being 0.49 versus >0.50) (Table 13).

In supportive analyses, 77.8% of participants in the Prevnar 20 group achieved a ≥4-fold rise in serotype 8 OPA titers from before vaccination to 1 month post-vaccination.

Immunobridging in Pneumococcal Vaccine Naïve Individuals 18 Through 59 Years of Age

In Study 1 (described above), the effectiveness of Prevnar 20 in individuals 50 through 59 years of age and in individuals 18 through 49 years of age was inferred following comparison of the immune response to each of the 20 vaccine serotypes in each of these age groups to the corresponding serotype-specific immune responses in individuals 60 through 64 years of age following Prevnar 20 (immunobridging). In Study 1, pneumococcal vaccine-naïve participants 50 through 59 years of age and 18 through 49 years of age were randomly assigned (3:1 ratio) to receive 1 vaccination with Prevnar 20 or Prevnar 13. Serotype-specific OPA GMTs were measured before vaccination and 1 month after vaccination. A comparative analysis of Prevnar 20 in the younger age group versus Prevnar 20 in individuals 60 through 64 years of age for each vaccine serotype was performed to support the indication in individuals 18 through 49 years of age and 50 through 59 years of age. Immunobridging was to be declared successful if the lower bound of the 2-sided 95% CI for the GMT ratio (Prevnar 20 in participants 18 through 49 years of age/60 through 64 years of age and in participants 50 through 59 years of age/60 through 64 years of age) for the 20 serotypes was >0.5 (2-fold). Prevnar 20 elicited serotype-specific immune responses to each of the 20 vaccine serotypes in both of the younger age groups that were within 2-fold of the corresponding serotype-specific responses in individuals 60 through 64 years of age, when measured 1 month after vaccination (Table 14).

Immunogenicity of Prevnar 20 in Individuals Previously Vaccinated With Pneumococcal Vaccine

A randomized, open-label clinical trial (Study 6) described immune responses to Prevnar 20 in individuals 65 years of age and older previously vaccinated with PPSV23 (≥1 to ≤5 years prior to enrollment), previously vaccinated with Prevnar 13 (≥6 months prior to enrollment), or previously vaccinated with Prevnar 13 followed by PPSV23 (with PPSV23 vaccination ≥1 year prior to enrollment). Participants in this clinical trial previously vaccinated with Prevnar 13 (Prevnar 13 only or followed by PPSV23) were enrolled at sites in the United States and participants previously vaccinated with PPSV23 only were also enrolled from Swedish sites (35.5% in that category). Immune responses elicited by Prevnar 20 were measured by an OPA assay.

OPA GMTs in participants who received PPSV23 1 to 5 years prior to Prevnar 20 were diminished compared to OPA GMTs in participants who received Prevnar 13 at least 6 months previously and compared to OPA GMTs in participants who received Prevnar 13 followed by PPSV23, with the last PPSV23 dose given at least 1 year prior to Prevnar 20.

14.4 Concomitant Vaccine Administration

Individuals 6 Weeks Through 15 Months of Age

In Study 8, the concomitant administration of Pediarix and Hiberix with each of the 3 infant doses of either Prevnar 20 or Prevnar 13 were evaluated 1 month after the third dose. Concomitant administration of single doses of M-M-R II and VARIVAX with the fourth dose of either Prevnar 20 or Prevnar 13 were evaluated 1 month following vaccination. There was no evidence that Prevnar 20, as compared to Prevnar 13, interfered with the antibody responses to these concomitantly administered vaccines.

Individuals 65 Years of Age and Older

Clinical Trial in Individuals to Assess Prevnar 20 Given With Influenza Vaccine, Adjuvanted (Fluad Quadrivalent)

Study 7 was a double-blind, randomized study conducted in individuals 65 years of age and older who had no history of prior pneumococcal vaccination or who had previously received PPSV23 and/or Prevnar 13 at least 6 months prior to enrollment. Study participants were randomized in a 1:1 ratio to receive Prevnar 20 concomitantly administered with Fluad Quadrivalent followed approximately one month later by placebo (Group 1, N=898) or Fluad Quadrivalent concomitantly administered with placebo followed approximately one month later by Prevnar 20 (Group 2, N=898). Pneumococcal serotype-specific OPA GMTs were evaluated 1 month after Prevnar 20 and influenza vaccine strain hemagglutinin inhibition assay (HAI) GMTs were evaluated 1 month after Fluad Quadrivalent. The noninferiority criteria for the comparisons of OPA GMTs (lower limit of the 2- sided 95% CI of the GMT ratio [Group 1/Group 2] >0.5, 2-fold noninferiority criterion) were met for all 20 pneumococcal serotypes in Prevnar 20. The noninferiority criteria for the comparisons of HAI GMTs (lower limit of the 2- sided 95% CI for the GMT ratio [Group 1/Group 2] >0.67, 1.5-fold noninferiority criterion) were also met for all 4 influenza vaccine strains.