Abrysvo Powder and solvent for solution for injection

Pharmacotherapeutic group: vaccines, other viral vaccines, ATC code: J07BX05 Mechanism of action Abrysvo contains two recombinant stabilized RSV prefusion F antigens representing RSV subgroups A and B.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ The prefusion F antigen is the primary target of neutralizing antibodies that block RSV infection. Following intramuscular administration, the prefusion F antigens elicit an immune response that protects against RSV-associated lower respiratory tract disease (LRTD). In infants born to mothers vaccinated with Abrysvo between gestational weeks 24 and 36, protection against RSV-associated LRTD results from transplacental transfer of RSV neutralizing antibodies. Adults aged 18 years and older are protected through active immunization. Clinical efficacy Infants from birth to 6 months of age through active immunization of pregnant individuals Clinical trial 1 was a multicenter, randomized (1:1), double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy of a single dose of Abrysvo in the prevention of RSV-associated LRTD in infants born to pregnant individuals vaccinated between gestational weeks 24 and 36. The need for revaccination in subsequent pregnancies has not been established. RSV-associated LRTD was defined as a medically attended visit in individuals with RSV confirmed by reverse transcription polymerase chain reaction (RT-PCR) and with one or more of the following respiratory signs: tachypnea, low oxygen saturation (SpO2 < 95%), and subcostal retractions. Severe RSV-associated LRTD was defined as illness meeting the criteria for RSV-associated LRTD and additionally at least one of the following criteria: very rapid breathing, low oxygen saturation (SpO2 < 93%), high-flow nasal cannula oxygen supplementation or mechanical ventilation, admission to an intensive care unit for > 4 hours, and/or unresponsiveness/unconsciousness. In this clinical trial, 3,711 pregnant individuals with uncomplicated singleton pregnancies were randomized to the Abrysvo group and 3,709 to the placebo group. Vaccine Efficacy (VE) was defined as the relative reduction in risk of the endpoint in the Abrysvo group compared with the placebo group for infants born to pregnant individuals who received the assigned intervention. In the primary analysis, two primary efficacy endpoints were evaluated in parallel: severe medically attended RSV-positive LRTD and medically attended RSV-positive LRTD occurring within 90, 120, 150, or 180 days after birth. Of the pregnant women who received Abrysvo, 65% were White, 20% were Black or African American, and 29% were Hispanic/Latino. The median age was 29 years (range 16–45 years); 0.2% of participants were younger than 18 years and 4.3% were younger than 20 years. The median gestational age at vaccination was 31 weeks and 2 days (range 24 weeks and 0 days to 36 weeks and 4 days). The median gestational age of infants at birth was 39 weeks and 1 day (range 27 weeks and 3 days to 43 weeks and 6 days). Vaccine efficacy is presented in Tables 2 and 3. Table 2 Vaccine efficacy of Abrysvo against severe medically attended RSV-associated LRTD in infants from birth to 6 months of age through active immunization of pregnant individuals – clinical trial 1 Time period Abrysvo Number of casesN = 3,495 Placebo Number of casesN = 3,480 % VE (CI) a 90 days 6 33 81.8 (40.6; 96.3) 120 days 12 46 73.9 (45.6; 88.8) 150 days 16 55 70.9 (44.5; 85.9) 180 days 19 62 69.4 (44.3; 84.1) CI = confidence interval, VE = vaccine efficacy a 99.5% CI at 90 days; 97.58% CI for later intervals Table 3 Vaccine efficacy of Abrysvo against medically attended RSV-associated LRTD in infants from birth to 6 months of age through active immunization of pregnant individuals – clinical trial 1 Time period Abrysvo Number of casesN = 3,495 Placebo Number of casesN = 3,480 % VE (CI) a 90 days 24 56 57.1 (14.7; 79.8) 120 days 35 81 56.8 (31.2; 73.5) 150 days 47 99 52.5 (28.7; 68.9) 180 days 57 117 51.3 (29.4; 66.8) CI = confidence interval, VE = vaccine efficacy a 99.5% CI at 90 days; 97.58% CI for later intervals A post hoc analysis of VE by maternal gestational age was conducted. For severe medically attended LRTD occurring within 180 days, VE was 57.2% (95% CI 10.4; 80.9) for women vaccinated in early pregnancy (24 to < 30 weeks) and 78.1% (95% CI 52.1; 91.2) for women vaccinated later in the eligible gestational period (30 to 36 weeks). For medically attended LRTD occurring within 180 days, VE for women vaccinated in early pregnancy (24 to < 30 weeks) was 30.9% (95% CI 14.4; 58.9) and 62.4% (95% CI 41.6; 76.4) for women vaccinated later in the eligible gestational period (30 to 36 weeks). Individuals aged 60 years and older Clinical trial 2 was a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy of Abrysvo in the prevention of RSV-associated LRTD in individuals aged 60 years and older. RSV-associated LRTD is defined as RT-PCR-confirmed RSV illness with two or more or three or more respiratory symptoms within 7 days of symptom onset, persisting for more than 1 day during the same illness: new or worsening cough, wheezing, sputum production, dyspnea, or tachypnea (≥ 25 breaths/min or 15% increase from resting baseline). Participants were randomized (1:1) to receive Abrysvo (n = 18,487) or placebo (n = 18,479). Enrollment was stratified by age: 60–69 years (63%), 70–79 years (32%), and ≥ 80 years (5%). Participants with stable chronic underlying conditions could be enrolled in this clinical trial, and 52% of participants had at least one prespecified condition; 16% of participants were enrolled with stable chronic cardiopulmonary conditions such as asthma (9%), chronic obstructive pulmonary disease (7%), or congestive heart failure (2%). Immunocompromised individuals could not be enrolled in the clinical trial. The primary objective was to evaluate vaccine efficacy (VE), defined as the relative reduction in risk of the first episode of RSV-associated LRTD in the Abrysvo group compared with the placebo group in the first RSV season. Of the participants who received Abrysvo, 51% were male, 80% were White, 12% were Black or African American, and 42% were Hispanic/Latino. The median age of participants was 67 years (range 59–95 years). At the end of the first RSV season, the analysis demonstrated statistically significant efficacy for Abrysvo in reducing RSV-associated LRTD with ≥ 2 symptoms and with ≥ 3 symptoms. Information on vaccine efficacy at the end of the first RSV season (median follow-up time 7.4 months) is presented in Table 4. Table 4 Vaccine efficacy of Abrysvo against RSV disease – active immunization of individuals aged 60 years and older – clinical trial 2 Efficacy endpoint Abrysvo Placebo VE (%) (95% CI) N n N n First episode of Overall 18,058 15 18,076 43 65.1 (35.9; 82.0) RSV-associated LRTD with ≥ 2 symptoms a Aged 60–69 years 11,305 10 11,351 25 60.0 (13.8; 82.9) Aged 70–79 years 5,750 4 5,742 12 66.7 (-10.0; 92.2) With ≥ 1 significant 9,377 8 9,432 22 63.6 (15.2; 86.0) underlying condition First episode of Overall 18,058 2 18,076 18 88.9 (53.6; 98.7) RSV-associated LRTD with ≥ 3 symptoms b Aged 60–69 years 11,305 2 11,351 11 81.8 (16.7; 98.0) Aged 70–79 years 5,750 0 5,742 4 100 (-51.5; 100.0) With ≥ 1 significant 9,377 2 9,432 11 81.8 (16.7; 98.0) underlying condition CI – confidence interval, RSV – respiratory syncytial virus, VE – vaccine efficacy N = number of participants; n = number of cases a In an exploratory analysis in RSV subgroup A (Abrysvo n = 3, placebo n = 16), VE was 81.3% (CI 34.5; 96.5) and in RSV subgroup B (Abrysvo n = 12, placebo n = 26), VE was 53.8% (CI 5.2; 78.8). b In an exploratory analysis in RSV subgroup A (Abrysvo n = 1, placebo n = 5), VE was 80.0% (CI -78.7; 99.6) and in RSV subgroup B (Abrysvo n = 1, placebo n = 12), VE was 91.7% (CI 43.7; 99.8). Vaccine efficacy in the subgroup of participants aged 80 years and older (995 participants in the Abrysvo group and 981 participants in the placebo group) could not be determined due to the low overall number of cases observed (7 cases of RSV-associated LRTD with ≥ 2 symptoms and 3 cases of RSV-associated LRTD with ≥ 3 symptoms). Efficacy against RSV-associated lower respiratory tract disease over 2 RSV seasons in individuals aged 60 years and older Over 2 RSV seasons with a median follow-up time of 16.4 months, VE against RSV-associated LRTD with ≥ 2 symptoms was 58.8% (95% CI 43.0; 70.6; 54 cases in the Abrysvo group and 131 cases in the placebo group) and with ≥ 3 symptoms was 81.5% (95% CI 63.3; 91.6; 10 cases in the Abrysvo group and 54 cases in the placebo group). VE against RSV-associated LRTD caused by RSV-A and RSV-B was 66.3% (95% CI 47.2; 79.0) and 50.0% (95% CI 18.5; 70.0), respectively, for cases with ≥ 2 LRTD symptoms, and 80.6% (95% CI 52.9; 93.4) and 86.4% (95% CI 54.6; 97.4), respectively, for cases with ≥ 3 LRTD symptoms. Over 2 RSV seasons, subgroup analyses of VE by age and significant underlying conditions were consistent with VE at the end of the first RSV season and support consistent VE across different age and risk groups. Immunogenicity in individuals aged 18 to 59 years Clinical trial 3 was a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the safety and immunogenicity of Abrysvo in individuals aged 18 to 59 years who were considered at high risk of developing severe RSV-associated LRTD. Individuals enrolled in clinical trial 3 had chronic pulmonary (including asthma), cardiovascular (excluding isolated hypertension), renal, hepatic, neurological, hematological, or metabolic disorders (including diabetes mellitus and hyper/hypothyroidism). Participants were randomized (2:1) to receive a single dose of Abrysvo (n = 437) or placebo (n = 217). With respect to age, race, and ethnicity, demographic characteristics in clinical trial 3 were generally similar between participants who received Abrysvo and those who received placebo. Fifty-three percent (53%) were aged 18 to 49 years and 47% were aged 50 to 59 years. The vaccine and placebo groups were similar with regard to the presence of at least one prespecified health condition, including 53% with ≥ 1 chronic pulmonary disease, 8% with ≥ 1 cardiovascular disease, 42% with diabetes, and 31% with ≥ 1 other condition (hepatic, renal, neurological, hematological, or other metabolic disease). Vaccine efficacy in individuals aged 18 to 59 years is inferred through immunobridging with clinical trial 2, in which vaccine efficacy was demonstrated in individuals aged 60 years and older. Non-inferiority criteria were met in high-risk individuals aged 18 to 59 years compared with a randomly selected immunogenicity subset of individuals (external control group) aged ≥ 60 years from clinical trial 2 for the geometric mean titer (GMT) ratio of RSV neutralizing antibodies based on the lower bounds of 2-sided 95% CIs > 0.667 (1.5-fold non-inferiority margin) and for the difference in seroresponse rates based on the lower bounds of 2-sided 95% CIs > -10% for both RSV A and RSV B. Table 5 Comparison of model-adjusted RSV neutralizing antibody GMT 1 month after vaccination with Abrysvo between high-risk individuals aged 18 to 59 years (clinical trial 3) and individuals aged 60 years and older (clinical trial 2) Clinical trial 3, high-risk individuals aged 18–59 years Clinical trial 2, ≥ 60 years ANCOVA comparison RSV subgroups n Adjusted GMT (95% CI) n Adjusted GMT (95% CI) Adjusted GMR (95% CI) A 435 41,097 (37,986; 44,463) 408 26,225 (24,143; 28,486) 1.57 (1.396; 1.759) B 437 37,416 (34,278; 40,842) 408 24,680 (22,504; 27,065) 1.52 (1.333; 1.725) CI – confidence interval; GMR – geometric mean ratio; GMT – geometric mean titer Table 6 Comparison of seroresponse rates by RSV neutralizing antibodies 1 month after vaccination with Abrysvo between high-risk individuals aged 18 to 59 years (clinical trial 3) and individuals aged 60 years and older (clinical trial 2) Clinical trial 3, high-risk individuals aged 18–59 years Clinical trial 2, ≥ 60 years Comparison RSV subgroups n/N (%) 95% CI n/N (%) 95% CI Difference (95% CI) A 405/435 (93) 90.3; 95.3 359/408 (88) 84.4; 91.0 5.1 (1.2; 9.2) B 408/437 (93) 90.6; 95.5 347/408 (85) 81.2; 88.4 8.3 (4.2; 12.6) CI – confidence interval Immunogenicity in immunocompromised individuals aged 18 years and older Clinical trial 4 (C3671023 substudy B) was an open-label, multicenter, single-arm phase 3 clinical trial to evaluate the safety and immunogenicity of Abrysvo in immunocompromised individuals aged ≥ 18 years. Participants had a history of solid organ transplantation (kidney, liver, lung, or heart) at least 3 months prior to enrollment; end-stage renal disease and hemodialysis; autoimmune inflammatory disorders with active immunomodulatory therapy; or advanced non-small cell lung cancer and were receiving active immunomodulatory therapy. Participants received 2 doses of Abrysvo administered 1 month apart. A single dose of Abrysvo was sufficient to elicit robust neutralizing responses that were approximately 8-fold or 9-fold higher than baseline neutralizing responses against RSV A and RSV B in participants aged ≥ 18 years with immunocompromising conditions (n = 188). Following the second dose of Abrysvo administered 1 month after the first dose, responses did not increase. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of clinical trials with Abrysvo in children aged 2 to 18 years for the prevention of RSV-associated lower respiratory tract disease (for information on paediatric use, see section 4.2).