Pharmacotherapeutic group: vaccines, pneumococcal vaccines.
ATC code: J07AL02.
Pharmacology: Pharmacodynamics: Mechanism of action: Apexxnar contains 20 pneumococcal capsular polysaccharides all conjugated to a CRM
197 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 both an enhanced antibody response and generation of memory B-cells, allowing for an anamnestic (booster) response on re-exposure to the bacterium.
Vaccination with Apexxnar induces serum antibody production and immunologic memory against the serotypes contained within the vaccine. In adults, the levels of circulating antibodies that correlate with protection against pneumococcal disease have not been clearly defined.
Clinical efficacy: No efficacy studies have been performed with Apexxnar.
Immunogenicity data: Apexxnar 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 Apexxnar 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 hospitalisation for worsening disease within 12 weeks before receiving the study vaccine.
In each study, immune responses elicited by Apexxnar and the control pneumococcal vaccines were measured by an opsonophagocytic activity (OPA) assay. OPA assays measure functional antibodies to
Streptococcus pneumoniae.
Comparison of immune responses of Apexxnar to Prevenar 13 and PPSV23: In a randomised, active-controlled, double-blind, non-inferiority clinical trial (Pivotal Study 1007) of Apexxnar 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 Apexxnar or control. Participants 60 years of age and older were randomised in a 1:1 ratio to receive Apexxnar (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 Apexxnar (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 geometric mean titres (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 Apexxnar to a control vaccine for a serotype was declared if the lower bound of the 2-sided 95% confidence interval (CI) for the GMT ratio (Apexxnar/Prevenar 13; Apexxnar/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 Apexxnar 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 Apexxnar in the matched serotypes compared to Prevenar 13 (Table 1), however the clinical relevance of these findings is unknown.
The immune responses induced by Apexxnar 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 1). The clinical relevance of this observation is unknown. Supportive analyses for other serotype 8 endpoints in the Apexxnar group showed favourable outcomes. These include a geometric mean fold rise (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 1.)
Click on icon to see table/diagram/image
Immunogenicity 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 Apexxnar 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 Apexxnar in the younger age group versus Apexxnar 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 (Apexxnar 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. Apexxnar 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 2).
While not planned as an active control for immunogenicity evaluations in the study, a post hoc descriptive analysis showed generally numerically lower OPA geometric mean titres 1 month after Apexxnar 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 2.)
Click on icon to see table/diagram/image
Immunogenicity of Apexxnar in adults previously vaccinated with pneumococcal vaccine: A Phase 3 randomised, open-label clinical trial (Study 1006) described immune responses to Apexxnar 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).
Apexxnar elicited immune responses to all 20 vaccine serotypes in participants 65 years of age and older with prior pneumococcal vaccination (Table 3). Immune responses were lower in participants in both groups who received prior PPSV23 vaccinations. (See Table 3.)
Click on icon to see table/diagram/image
Concomitant vaccine administration: Clinical trial in adults to assess Apexxnar given with influenza vaccine, adjuvanted (Fluad Quadrivalent [QIV]): In a double-blind, randomised study B7471004 (Study 1004), adults 65 years of age and older were randomised in a 1:1 ratio to receive Apexxnar concomitantly administered with an influenza vaccine, adjuvanted (Fluad Quadrivalent [QIV]) (Group 1, N=898) or Apexxnar administered 1 month after receiving QIV (Group 2, N=898). Pneumococcal serotype-specific OPA GMTs were evaluated 1 month after Apexxnar and influenza vaccine strain hemagglutinin inhibition assay (HAI) GMTs were evaluated 1 month after QIV. 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 Apexxnar. 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.
Clinical trial in adults to assess Apexxnar given with a third (booster) dose of COVID-19 mRNA vaccine (nucleoside modified): In a double-blind, randomised descriptive study B7471026 (Study 1026), adults 65 years of age and older who had received 2 doses of COVID-19 mRNA vaccine (nucleoside modified) at least 6 months earlier, were randomized in a 1:1:1 ratio to receive Apexxnar concomitantly administered with a third (booster) dose of COVID-19 mRNA vaccine (nucleoside modified) (N=190), Apexxnar administered alone (N=191), or a third (booster) dose of COVID-19 mRNA vaccine (nucleoside modified) administered alone (N=189).
Immune responses to both vaccines were observed after co-administration of Apexxnar and COVID-19 mRNA vaccine (nucleoside modified). OPA GMTs for the 20 pneumococcal serotypes were similar to Apexxnar administered alone and IgG GMCs for the full-length S-binding protein were similar to COVID-19 mRNA vaccine (nucleoside modified) administered alone. A post-hoc analysis found the immune responses to all 20 serotypes elicited by Apexxnar when co-administered with COVID-19 mRNA vaccine (nucleoside modified) would have met conventional 2-fold noninferiority criteria compared to Apexxnar alone. Additionally, the full-length S-binding IgG GMC and reference strain neutralizing GMT elicited by COVID-19 mRNA vaccine (nucleoside modified) would have met conventional 1.5-fold noninferiority criteria compared to COVID-19 mRNA vaccine (nucleoside modified) alone.
Immune responses in special populations: Individuals with the conditions described as follows have an increased risk of pneumococcal disease.
Studies in HIV and bone marrow transplant participants have not been conducted with Apexxnar.
Limited experience from clinical studies with Prevenar 13 (a pneumococcal conjugate vaccine consisting of 13 polysaccharide conjugates that are also in Apexxnar) are available in adults with HIV infection, and adults following a bone marrow transplant.
Participants who were healthy, or with stable non-immunocompromising chronic medical conditions, in all the age groups analysed had a lower immune response with Apexxnar compared with Prevenar 13 in spite of meeting the predefined non-inferiority margins. The clinical relevance of this observation is unknown.
HIV infection: Adults not previously vaccinated with a pneumococcal vaccine: In Study 6115A1-3002 (B1851021), 152 HIV-infected participants 18 years of age and older (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 131 to 137 evaluable participants approximately 1 month after each dose of the vaccine. After the first dose, Prevenar 13 elicited antibody levels, measured by immunoglobulin G (IgG) geometric mean concentrations (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 and older (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.
Hematopoietic stem cell transplant (HSCT): In Study 6115A1-3003 (B1851022), 190 participants 18 years of age and older 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 130 to 159 evaluable participants 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.
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.
Paediatric population: The safety and efficacy of Apexxnar in children and adolescents younger than 18 years of age have not been established. No data are available.
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.