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Pharmacology: Pharmacodynamics: Mechanism of action: Prevenar 20 contains 20 pneumococcal capsular polysaccharides all conjugated to CRM197 carrier protein, which modifies the immune response to the polysaccharide from a T-cell independent response to a T-cell dependent response. The T-cell dependent response leads to an enhanced antibody response and induced functional antibodies (associated with opsonisation, phagocytosis and killing of pneumococci) to protect against pneumococcal disease, as well as the generation of memory B cells, allowing for an anamnestic (booster) response on re-exposure to the bacterium.
Immune responses in children and adults, after exposure to Streptococcus pneumoniae or following pneumococcal vaccination, can be determined by measuring IgG or opsonophagocytic activity (OPA) responses. OPA measures functional antibody activity and is considered to be an important immunologic surrogate measure of protection against pneumococcal disease in adults. In children, multiple immunogenicity criteria are used for the clinical evaluation of pneumococcal conjugate vaccines including the proportion of vaccinated children achieving a serotype-specific IgG antibody level corresponding to ≥0.35 μg/mL using the WHO enzyme linked immunosorbent assay (ELISA) or an equivalent assay-specific value.
Serotype-specific immune responses that correlate with individual protection against pneumococcal disease have not been clearly defined.
Clinical efficacy: No efficacy studies have been performed with Prevenar 20.
Immunogenicity data: Prevenar 20 clinical trials in infants, children and adolescents: Immunogenicity was assessed by serotype-specific IgG response rates (the proportion of participants meeting the serotype-specific IgG level of ≥0.35 μg/mL or equivalent assay-specific value) and IgG GMCs at 1 month following the primary series and 1 month following the toddler dose. OPA GMTs were also measured 1 month following the primary series and following the toddler dose. The predefined concentration corresponding to 0.35 μg/mL in the WHO ELISA (or equivalent assay-specific threshold value) is only applicable at the population level and cannot be used to predict individual or serotype-specific protection against IPD. No correlate of protection exists for pneumonia and acute otitis media (AOM).
Two Phase 3 clinical trials (Study 1011, Study 1012) and one Phase 2 clinical trial (Study 1003) evaluated the immunogenicity of Prevenar 20 in a 3-dose or a 4-dose series in infants. One Phase 3 Study B7471027 (Study 1027) evaluated the immunogenicity of a single booster dose or 2 doses of Prevenar 20 in toddlers 12 months to less than 24 months of age after 2 prior infant doses of Prevenar 13. One Phase 3 study (Study 1014) of children 15 months to less than 18 years of age evaluated a single dose of Prevenar 20.
Immune responses following 3 and 4 doses in a 4-dose infant vaccination series: In Study 1011, conducted in the United States and Puerto Rico, 1,991 healthy infants aged 2 months (≥42 to ≤98 days) at the time of consent and born at >36 weeks of gestation, were randomised (1:1) and vaccinated with either Prevenar 20 or Prevenar 13 at approximately 2, 4, 6, and 12 to 15 months of age. Participants also received other paediatric vaccines including a combination vaccine containing diphtheria, tetanus, pertussis (acellular), hepatitis B (rDNA), poliomyelitis (inactivated), and a Haemophilus influenzae type b conjugate vaccine (adsorbed) with all 3 doses, and measles, mumps, rubella combination vaccine, and varicella vaccine at the toddler dose. Rotavirus and influenza vaccines were permitted to be co-administered in the study.
One month after the third infant dose, NI for the difference in percentages of participants with specified serotype-specific IgG concentrations (with a 10% NI criterion) was met for 9 of the 13 matched serotypes and missed for 4 serotypes (serotypes 3, 4, 9V, and 23F) (Table 1). Six of the 7 additional serotypes also met the non-inferiority criterion when compared to the lowest result for a vaccine serotype in the Prevenar 13 group (excluding serotype 3); serotype 12F missed the statistical non-inferiority criterion. IgG GMCs 1 month after dose 3 of Prevenar 20 were non-inferior (with a 0.5 NI criterion for IgG geometric mean ratio (GMR)) to those in the Prevenar 13 group for all 13 matched serotypes. The NI criterion was also met for the 7 additional serotypes to the lowest IgG GMC (excluding serotype 3) among the vaccine serotypes in the Prevenar 13 group (Table 1).
The antibody levels for all 7 additional serotypes were significantly higher than the corresponding serotype in the Prevenar 13 group (Tables 1 and 2).
One month after the toddler dose, NI for IgG GMCs (with a 0.5 NI criterion for IgG GMR) was met for all 13 matched serotypes. The NI criterion was also met for the 7 additional serotypes to the lowest IgG GMC (excluding serotype 3) among the vaccine serotypes in the Prevenar 13 group (Table 2). Although non-inferiority was not formally tested for this endpoint, the observed differences (Prevenar 20 - Prevenar 13) in percentages of participants with specified serotype-specific IgG concentrations 1 month after dose 4 were greater than -10% for all 13 matched serotypes except serotype 3 (-16.4%, CI -21.0%, -11.8%). For the 7 additional serotypes, the observed differences in percentage of participants with specified serotype-specific IgG concentrations 1 month after dose 4 ranged from -11.5% (serotype 12F) to 1.8% (serotype 15B, 22F, and 33F) (Table 2). (See Tables 1 and 2.)
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Click on icon to see table/diagram/imageOPA GMTs for the 13 matched serotypes in the Prevenar 20 group were generally comparable to the OPA GMTs in the Prevenar 13 group 1 month after the third infant dose, and they were slightly lower than in the Prevenar 13 group for most serotypes after the toddler dose. There is variability of the OPA data due to small sample sizes, while interpretation of the clinical relevance of slightly lower OPA GMTs is unknown. The observed OPA GMTs for the 7 additional serotypes were substantially higher in the Prevenar 20 group than the Prevenar 13 group. Prevenar 20 immune responses also show boosting of IgG concentrations and OPA GMTs after the toddler dose, indicating that a memory response was elicited by the 3 infant doses.
Pneumococcal IgG immune responses following 2 and 3 doses of 3-dose vaccination series: In Study 1012, 1,204 infants 2 months (≥42 to ≤112 days) of age at the time of consent and born at >36 weeks of gestation were randomised (1:1) and vaccinated with either Prevenar 20 or Prevenar 13. The first dose was given at enrollment, a second dose approximately 2 months later, and the third dose at approximately 11 to 12 months of age.
One month after 2 infant doses, the observed IgG GMCs for 9 of the 13 matched serotypes were noninferior to those in the Prevenar 13 group, and 4 of the 13 matched serotypes (6A, 6B, 9V, and 23F) did not meet the 2-fold statistical criterion for non-inferiority. The percentages of participants with specified serotype-specific IgG concentrations 1 month after Dose 2 of Prevenar 20 for 4 of the 13 matched serotypes were non-inferior to those of the Prevenar 13 group based on a 10% difference non-inferiority criteria; and 9 of the 13 matched serotypes (1, 3, 4, 5, 6A, 6B, 9V, 18C and 23F) did not meet noninferiority.
The immune responses to the additional 7 serotypes after Prevenar 20 were non-inferior to the lowest IgG GMC among the 13 serotypes (serotype 6B) in Prevenar 13. For the 7 additional serotypes, the percentages of participants with specified serotype-specific IgG concentrations 1 month after Dose 2 of Prevenar 20 for 5 of the 7 additional serotypes were non-inferior to the serotype with the lowest percentage among the 13 serotypes (serotype 6B) in the Prevenar 13 group and serotypes 10A and 12F did not meet the statistical noninferiority criterion. The clinical relevance of these findings is unknown. Additionally, the IgG GMCs for the 7 additional serotypes were higher compared with the IgG GMCs from the corresponding serotypes in the Prevenar 13 group after two infant doses. One month after the third (toddler) dose, the observed IgG GMCs of Prevenar 20 were non-inferior to the Prevenar 13 group for 12 of 13 matched serotypes except for serotype 6B and all 7 additional serotypes were non-inferior to the lowest IgG GMC in the Prevenar 13 group. Additionally, the IgG GMCs for the 7 additional serotypes were higher compared with the IgG GMCs from the corresponding serotypes in the Prevenar 13 group after the toddler dose.
Functional responses, as measured by OPA GMTs, for the 13 matched serotypes at 1 month after the second infant dose and 1 month after the toddler dose in the Prevenar 20 group were generally similar to the observed OPA GMTs in the Prevenar 13 group for most serotypes and the observed OPA GMTs were substantially higher for the 7 additional serotypes at both timepoints in the Prevenar 20 group than in the Prevenar 13 group. Increases in IgG and OPA antibody responses after Prevenar 20 following Dose 2 to after Dose 3 were observed for all 20 serotypes including those that missed non-inferiority, indicative of immunological memory.
Children 12 months to less than 18 years of age (Studies 1027 and 1014): Children 12 months to less than 24 months of age previously vaccinated with Prevenar 13: (Study 1027) In a multicentre, randomised, partially double-blinded trial (Study 1027), 356 participants 12 months to less than 24 months of age with 2 prior infant doses of Prevenar 13 were enrolled and randomised to receive either 1 or 2 toddler doses of Prevenar 20, or a single dose of Prevenar 13 (control). In the group receiving 2 doses of Prevenar 20, the second dose was given approximately 2 months after Dose 1.
IgG immune responses to the 13 matched serotypes were observed after 1 or 2 doses of Prevenar 20 with the observed IgG GMCs numerically higher for most of the 13 matched serotypes after 1 dose of Prevenar 20 than after 2 doses of Prevenar 20. The observed IgG GMCs 1 month after last vaccination for the 13 matched serotypes were lower after 1 or 2 doses of Prevenar 20 than after 1 dose of Prevenar 13. IgG immune responses to all 7 additional serotypes were observed after 1 or 2 doses of Prevenar 20, with numerically higher IgG responses after 2 doses of Prevenar 20 than after a single dose. The observed IgG GMCs for all 7 additional serotypes (not covered by Prevenar 13) were low 1 month after a single toddler dose of Prevenar 13.
OPA responses were elicited for all 20 serotypes with similar tendencies as described previously for IgG GMCs.
Children and adolescents 15 months to less than 18 years of age (Study 1014): In a multicentre, single-arm trial (Study 1014), participants were enrolled into the study by age group (approximately 200 participants per group) to receive a single dose of Prevenar 20 as described as follows.
Children 15 months to less than 24 months of age previously vaccinated with Prevenar 13: In 15 months to less than 24 months age group, participants had been previously vaccinated with 3 or 4 doses of Prevenar 13. Increases in IgG concentrations from before to 1 month after Prevenar 20 were observed for all 20 vaccine serotypes. The observed IgG geometric mean fold rises (GMFRs) to the 7 additional serotypes ranged from 27.9 to 1847.7.
Children 24 months to less than 5 years of age previously vaccinated with Prevenar 13: In 24 months to less than 5 years age group, participants had been previously vaccinated with 3 or 4 doses of Prevenar 13. Increases in IgG concentrations from before to 1 month after Prevenar 20 were observed for all 20 vaccine serotypes. The observed IgG GMFRs to the 7 additional serotypes ranged from 36.6 to 796.2. For the 7 additional serotypes, 71.2% to 94.6% had ≥4-fold rise in OPA titres.
Children and adolescents 5 years to less than 18 years of age previously unvaccinated or vaccinated with Prevenar 13: In participants 5 years to less than 10 years and 10 years to less than 18 years of age, irrespective of prior vaccination history with Prevenar 13. Prevenar 20 elicited robust IgG and OPA immune responses to the 20 vaccine serotypes after a single dose in participants 5 to less than 18 years of age. OPA GMFRs ranged from 11.5 to 499.0 to the 7 additional serotypes and increases in OPA GMTs were observed for all 20 vaccine serotypes.
Preterm infants: No immunogenicity data is available with Prevenar 20 in preterm infants. Based on experience with Prevenar and Prevenar 13, immune responses are elicited in preterm infants, although they may be lower than in term infants. The safety and tolerability of Prevenar 20 were evaluated in Phase 3 study (Study 1013), which included 111 late preterm infants (infants born at 34 to less than 37 weeks of gestational age) among the total study population. Participants were randomised to receive a 4-dose series of either Prevenar 20 (N=77) or Prevenar 13 (N=34).
Prevenar 20 clinical trials in adults: Three Phase 3 clinical trials, B7471006, B7471007 and B7471008 (Study 1006, Study 1007, and Study 1008), were conducted in the United States and Sweden evaluating the immunogenicity of Prevenar 20 in different adult age groups, and in participants who were either pneumococcal vaccine-naïve, or previously vaccinated with Prevenar 13, PPSV23, or both.
Each study included participants who were healthy or immunocompetent with stable underlying conditions, including chronic cardiovascular disease, chronic pulmonary disease, renal disorders, diabetes mellitus, chronic liver disease, and medical risk conditions and behaviours (e.g., smoking) that are known to increase the risk of serious pneumococcal pneumonia and IPD. In the pivotal study (Study 1007), these risk factors were identified in 34%, 32%, and 26% of participants 60 years of age and over, 50 to 59 years of age, and 18 to 49 years of age, respectively. 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 receiving the study vaccine.
In each study, immune responses elicited by Prevenar 20 and the control pneumococcal vaccines were measured by an opsonophagocytic activity (OPA) assay. OPA assays measure functional antibodies to S. pneumoniae.
Comparison of immune responses of Prevenar 20 to Prevenar 13 and PPSV23: In a randomised, active-controlled, double-blind, non-inferiority clinical trial (Pivotal Study 1007) of Prevenar 20 in the United States and Sweden, pneumococcal vaccine-naïve participants 18 years of age and older were enrolled into 1 of 3 cohorts based on their age at enrollment (18 to 49, 50 to 59, and ≥60 years of age), and randomised to receive Prevenar 20 or control. Participants 60 years of age and older were randomised in a 1:1 ratio to receive Prevenar 20 (n=1,507) followed 1 month later with the administration of saline placebo or Prevenar 13 (n=1,490), and with the administration of PPSV23 1 month later. Participants 18 to 49 years of age and 50 to 59 years of age were randomly assigned (3:1 ratio); they received a dose of Prevenar 20 (18 to 49 years of age: n=335; 50 to 59 years of age: n=334) or Prevenar 13 (18 to 49 years of age: n=112; 50 to 59 years of age: n=111).
Serotype-specific OPA GMTs were measured before the first vaccination and 1 month after each vaccination. Non-inferiority of immune responses, OPA GMTs 1 month after vaccination, with Prevenar 20 to a control vaccine for a serotype was declared if the lower bound of the 2-sided 95% CI for the GMT ratio (Prevenar 20/Prevenar 13; Prevenar 20/PPSV23) for that serotype was greater than 0.5.
In participants 60 years of age and older, the immune responses to all 13 matched serotypes elicited by Prevenar 20 were non-inferior to those elicited by Prevenar 13 for the same serotypes 1 month after vaccination. In general, numerically lower geometric mean titres were observed with Prevenar 20 in the matched serotypes compared to Prevenar 13 (Table 3), however the clinical relevance of these findings is unknown.
The immune responses induced by Prevenar 20 to 6/7 additional serotypes were non-inferior to those induced by PPSV23 to the same serotypes 1 month after vaccination. The response to serotype 8 missed the pre-specified statistical non-inferiority criterion (the lower bound of the 2-sided 95% CI for the GMT ratio is 0.49 instead of >0.50) (Table 3). The clinical relevance of this observation is unknown. Supportive analyses for other serotype 8 endpoints in the Prevenar 20 group showed favourable outcomes. These include a GMFR of 22.1 from before vaccination to 1 month post-vaccination, 77.8% of participants achieved a ≥4-fold rise in OPA titres from before vaccination to 1 month after vaccination, and 92.9% of participants achieved OPA titres ≥LLOQ 1 month after vaccination. (See Table 3.)
Click on icon to see table/diagram/imageImmunogenicity in participants 18 through 59 years of age: In Study 1007, participants 50 through 59 years of age and participants 18 through 49 years of age were randomly assigned (3:1 ratio) to receive 1 vaccination with Prevenar 20 or Prevenar 13. Serotype-specific OPA GMTs were measured before vaccination and 1 month after vaccination. With both vaccines, higher immune responses were observed in younger participants compared with older participants. A non-inferiority analysis of Prevenar 20 in the younger age group versus Prevenar 20 in participants 60 through 64 years of age per serotype was performed to support the indication in adults 18 through 49 years of age and 50 through 59 years of age. Non-inferiority was declared if the lower bound of the 2-sided 95% CI for the GMT ratio (Prevenar 20 in participants 18 through 49 years of age/60 through 64 years of age and in 50 through 59 years of age/60 through 64 years of age) for each of the 20 serotypes was >0.5. Prevenar 20 elicited immune responses to all 20 vaccine serotypes in the two of the younger age groups that were non-inferior to responses in participants 60 through 64 years of age 1 month after vaccination (Table 4).
While not planned as an active control for immunogenicity evaluations in the study, a post hoc descriptive analysis showed generally numerically lower OPA GMTs 1 month after Prevenar 20 for the matched serotypes compared to Prevenar 13 in participants 18 through 59 years of age, however the clinical relevance of these findings is unknown.
As noted previously, individuals with risk factors were included in this study. Across all the age groups studied, in general, a numerically lower immune response was observed in participants with risk factors compared to participants without risk factors. The clinical relevance of this observation is unknown. (See Table 4.)
Click on icon to see table/diagram/imageImmunogenicity of Prevenar 20 in adults previously vaccinated with pneumococcal vaccine: A Phase 3 randomised, open-label clinical trial (Study 1006) described immune responses to Prevenar 20 in participants 65 years of age and older previously vaccinated with PPSV23, with Prevenar 13, or with Prevenar 13 followed by PPSV23. Participants previously vaccinated with Prevenar 13 (Prevenar 13 only or followed by PPSV23) were enrolled at sites in the United States, whereas participants and previously vaccinated with PPSV23 only were also enrolled from Swedish sites (35.5% in that category).
Prevenar 20 elicited immune responses to all 20 vaccine serotypes in participants 65 years of age and older with prior pneumococcal vaccination (Table 5). Immune responses were lower in participants in both groups who received prior PPSV23 vaccinations. (See Table 5.)
Click on icon to see table/diagram/imageImmune responses in special populations: Individuals with the conditions described as follows have an increased risk of pneumococcal disease.
Studies in individuals with SCD, HIV, and HSCT have not been conducted with Prevenar 20.
Experience from clinical studies with Prevenar 13 (a pneumococcal conjugate vaccine consisting of 13 polysaccharide conjugates that are also in Prevenar 20) are available in children and adults at higher risk of pneumococcal infection including immunocompromised children and adults with HIV infection or HSCT, and children with SCD.
Participants who were healthy, or with stable non-immunocompromising chronic medical conditions, in all the age groups analysed had a lower immune response with Prevenar 20 compared with Prevenar 13 in spite of meeting the predefined non-inferiority margins. The clinical relevance of this observation is unknown.
Sickle cell disease (SCD): An open-label single-arm study with 2 doses of Prevenar 13 given 6 months apart was conducted in 158 children and adolescents 6 to <18 years of age with SCD who were previously vaccinated with one or more doses of 23-valent pneumococcal polysaccharide vaccine 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 significantly higher when compared with levels prior to vaccination. After the second dose, immune responses were comparable to those after the first dose. One year after the second dose, antibody levels measured by both IgG GMCs and OPA GMTs were higher than levels prior to the first dose of Prevenar 13, except for the IgG GMCs for serotypes 3 and 5 that were numerically similar.
HIV infection: Children and adults not previously vaccinated with a pneumococcal vaccine: In Study 6115A1-3002 (B1851021), 151 participants 6 to <18 years of age and 152 participants ≥18 years of age infected with HIV (CD4 ≥200 cells/μL, viral load <50,000 copies/mL and free of active acquired immunodeficiency syndrome [AIDS]-related illness) not previously vaccinated with a pneumococcal vaccine were enrolled to receive 3 doses of Prevenar 13. As per the general recommendations, a single dose of PPSV23 was subsequently administered. The vaccines were administered at 1-month intervals. Immune responses were assessed in 128 to 133 evaluable participants 6 to <18 years of age and in 131 to 137 evaluable participants ≥18 years of age approximately 1 month after each dose of the vaccine. After the first dose, Prevenar 13 elicited antibody levels, measured by IgG GMCs and OPA GMTs, that were statistically significantly higher compared with levels prior to vaccination. After the second and third dose of Prevenar 13, immune responses were similar to or higher than those after the first dose.
Adults previously vaccinated with PPSV23: In Study 6115A1-3017 (B1851028), immune responses were assessed in 329 HIV-infected participants ≥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. Participants 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 IgG GMCs and OPA GMTs that were statistically significantly higher compared with levels prior to vaccination. After the second and third dose of Prevenar 13, immune responses were comparable to or higher than those after the first dose. Participants who received previously 2 or more doses of PPSV23 showed a similar immune response compared to participants who previously received a single dose.
Haematopoietic stem cell transplant (HSCT): In Study 6115A1-3003 (B1851022), 61 participants 2 to <18 years of age and 190 participants ≥18 years of age with an allogeneic HSCT were enrolled to receive 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 the 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 41 to 52 evaluable participants 2 to <18 years of age and in 127 to 159 evaluable participants ≥18 years of age approximately 1 month after vaccination. Prevenar 13 elicited increased antibody levels after each dose. Immune responses after the fourth dose of Prevenar 13 were significantly increased for all serotypes compared with those after the third dose with the exception of serotype 3 in the 2 to <18 years age group. Overall, participants 2 to <18 years of age had generally higher serotype-specific immune responses compared with those ≥18 years of age.
This study demonstrated that 4 doses of Prevenar 13 elicited serum IgG concentrations similar to those induced by a single dose in healthy participants of the same age group.
Invasive pneumococcal disease (IPD): Vaccine effectiveness of Prevenar 13 against vaccine-serotype IPD was evaluated in the SpIDnet study, a multi-country enhanced IPD surveillance project in Europe. Based on data over a 6-year period (2012-2018) from 10 sites in 7 European countries using Prevenar 13, the effectiveness against IPD caused by serotypes in the vaccine among children <5 years of age was 84.2% (95% CI, 79.0-88.1) and 88.7% (95% CI, 81.7-92.7) in children receiving ≥1 Prevenar 13 dose and a complete vaccination schedule, respectively.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity and reproduction and developmental toxicity.
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