AREXVY Powder for suspension for injection Ref.[50990] Active ingredients: Respiratory syncytial virus vaccine

Pharmacotherapeutic group: Vaccines, other viral vaccines
ATC code: J07BX05

Mechanism of action

By combining the RSV-specific antigen, F-protein in prefusion conformation, with an adjuvant system (AS01_E), Arexvy is designed to enhance antigen-specific cellular immune response and neutralizing antibodies response in individuals with pre-existing immunity against RSV. The adjuvant AS01_E facilitates the recruitment and activation of antigen presenting cells carrying vaccine-derived antigens in the draining lymph node, which in turn leads to the generation of RSVPreF3-specific CD4+ T cells.

Efficacy

Efficacy against RSV-associated LRTD in adults 60 years and older was evaluated in an ongoing, Phase III, randomised, placebo-controlled, observer-blind clinical study conducted in 17 countries from Northern and Southern Hemispheres. Participants are planned to be followed for up to 36 months.

The primary population for efficacy analysis (referred to as the modified Exposed Set, defined as adults 60 years of age and older who received 1 dose of Arexvy or placebo and who did not report an RSV-confirmed acute respiratory illness [ARI] prior to Day 15 after vaccination) included 24 960 participants randomised equally to receive 1 dose of Arexvy (N=12 466) or placebo (N=12 494). At the time of the first confirmatory efficacy analysis, participants had been followed for the development of RSV-associated LRTD for a median of 6.7 months.

The median age of participants was 69 years (range: 59 to 102 years), with approximately 74% over 65 years of age, approximately 44% over 70 years of age and approximately 8% over 80 years of age. Approximately 52% were female. At baseline, 39.3% of participants had at least one comorbidity of interest; 19.7% of participants had an underlying cardiorespiratory condition (COPD, asthma, any chronic respiratory/pulmonary disease, or chronic heart failure) and 25.8% of participants had endocrinometabolic conditions (diabetes, advanced liver or renal disease).

Efficacy against RSV-associated LRTD during the first RSV season (confirmatory analysis)

The primary objective was to demonstrate efficacy in the prevention of a first episode of confirmed RSV-A and/or B associated LRTD during the first RSV season. Confirmed RSV cases were determined by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) on nasopharyngeal swab. LRTD was defined based on the following criteria: the participant must have experienced at least 2 lower respiratory symptoms/signs including at least 1 lower respiratory sign for at least 24 hours, or experienced at least 3 lower respiratory symptoms for at least 24 hours. Lower respiratory symptoms included: new or increased sputum, new or increased cough, new or increased dyspnoea (shortness of breath). Lower respiratory signs included: new or increased wheezing, crackles/rhonchi, respiratory rate ≥20 respirations/min, low or decreased oxygen saturation (O₂ saturation <95% or ≤90% if baseline is <95%) or need for oxygen supplementation.

The vaccine efficacy overall and by subgroups is presented in Table 2.

Efficacy in preventing first RSV-associated LRTD with an onset from 15 days after vaccination compared to placebo was 82.6% (96.95% confidence interval of 57.9% to 94.1%) in participants 60 years of age and older. Vaccine efficacy against RSV-LRTD was observed through the median follow-up period of 6.7 months. Vaccine efficacy against RSV A-associated LRTD cases and RSV B-associated LRTD cases was 84.6% (95% CI [32.1, 98.3]) and 80.9% (95% CI [49.4, 94.3]), respectively.

Table 2. Efficacy analysis during the first RSV season (confirmatory analysis): First RSV-associated LRTD overall, by age and co-morbidity subgroups (modified exposed set):

^a CI = Confidence Interval (96.95% for the overall (≥ 60 years) and 95% for all subgroup analyses). Two-sided exact CI for vaccine efficacy is derived based on Poisson model adjusted by age categories and regions.
^b Primary confirmatory objective with pre-specified success criterion of lower limit of the 2-sided CI for vaccine efficacy above 20%
N = Number of participants included in each group
n = Number of participants having first occurrence of RSV-confirmed LRTD occurring from Day 15 post vaccination

The vaccine efficacy in the subgroup of participants 80 years of age and older (1 016 participants in Arexvy vs 1 028 participants in placebo) cannot be concluded due to the low number of total cases accrued (5 cases).

Amongst 18 RSV-LRTD cases with at least 2 lower respiratory signs or preventing everyday activities, 4 cases of severe RSV-LRTD requiring oxygen supplementation occurred in the placebo group compared to none in the Arexvy group.

Efficacy against RSV-associated LRTD over 2 RSV seasons

Over 2 RSV seasons (up to end of second season in Northern Hemisphere), with a median follow-up time of 17.8 months, vaccine efficacy against RSV-associated LRTD was 67.2% (97.5% CI [48.2, 80.0]) in participants 60 years of age and older (30 cases in the Arexvy group and 139 cases in the placebo group).

Vaccine efficacy against RSV-associated LRTD was similar in the subgroup of participants with at least one comorbidity of interest.

A second dose of vaccine administered 12 months after the first dose did not confer additional efficacy benefit.

Immunogenicity in adults 50 through 59 years of age at increased risk for RSV disease

The non-inferiority of the immune response to Arexvy in adults 50 through 59 years of age compared to adults 60 years of age and older, where vaccine efficacy against RSV-associated LRTD was demonstrated, was evaluated in a Phase III, observer-blind, randomised, placebo-controlled study.

Cohort 1 consisted of participants 50 through 59 years of age separated in 2 sub-cohorts (Adults-AIR and Adults-non-AIR) according to their medical history. Adults-AIR (adults at increased risk) sub-cohort consisted of participants with pre-defined, stable, chronic medical conditions leading to an increased risk for RSV disease (Arexvy, N=386; placebo, N=191) such as chronic pulmonary disease, chronic cardiovascular disease, diabetes, chronic kidney or liver disease. Adults-non-AIR sub-cohort consisted of participants without pre-defined, stable, chronic medical conditions (Arexvy, N=383; placebo, N=192). Cohort 2 (OA; older adults) consisted of participants 60 years of age and older (Arexvy, N=381).

The primary immunogenicity objectives were to demonstrate non-inferiority of the humoral immune response (in terms of RSV-A and RSV-B neutralising titers) following the administration of Arexvy at 1-month post-vaccination in participants 50 through 59 years of age with and without pre-defined, stable, chronic medical conditions leading to an increased risk for RSV disease, compared to participants 60 years of age and older.

Table 3. Summary of adjusted GMT and SRR values, and adjusted GMT ratios and SRR differences in terms of RSV-A and RSV-B neutralising titers (ED60) in adults 60 years of age and older (OA) relative to adults 50 through 59 years of age with (Adults-AIR) and without (Adults-non-AIR) pre-defined, stable, chronic medical conditions^a leading to an increased risk for RSV disease – Per Protocol Set:

^a Pre-defined, stable, chronic medical conditions such as chronic pulmonary disease, chronic cardiovascular disease, diabetes, chronic kidney or liver disease.
^b,c The prespecified criteria for non-inferiority of the immune responses were defined as the 2-sided 95% or 97.5% CI upper limits (UL) on the adjusted GMT ratios (OA over Adults-AIR or Adults-non-AIR) ≤1.5 and the UL of the 2-sided 95% or 97.5% CI on the SRR difference (OA minus Adults-AIR or Adults-non-AIR) ≤10% in participants 60 years of age and older (OA) relative to participants 50 through 59 years of age with (Adults-AIR) or without (Adults-non-AIR) pre-defined, stable, chronic medical conditions leading to an increased risk for RSV disease
ED60: Estimated dilution 60; CI = Confidence interval; GMT = Geometric mean titer; SRR = Seroresponse rate

The non-inferiority criteria of the immune responses for the RSV-A and RSV-B neutralising titers were met. The efficacy of Arexvy, in adults 50 through 59 years of age at increased risk for RSV disease, can be inferred following comparison of the immune response in adults 50 through 59 years of age with the immune response in adults 60 years of age and older in whom vaccine efficacy was demonstrated.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Arexvy in one or more subsets of the paediatric population in prevention of lower respiratory tract disease caused by respiratory syncytial virus (see section 4.2 for information on paediatric use).