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Pharmacology: Pharmacodynamics: Mechanism of action: By combining the RSV-specific antigen, F-protein in prefusion conformation, with an adjuvant system (AS01E), Arexvy is designed to enhance antigen-specific cellular immune response and neutralizing antibodies response in individuals with pre-existing immunity against RSV. The adjuvant AS01E 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 lower respiratory tract disease (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, included adults 60 years of age and older receiving 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 primary 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 over the first RSV season: The primary objective was to demonstrate the efficacy in the prevention of a first episode of confirmed RSV-A and/or B associated LRTD during the first 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 dyspnea (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 1.
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. The 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. (See Table 1.)
Click on icon to see table/diagram/imageThe 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, while there were 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, the 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).
Subgroup analyses of RSV-associated LRTD vaccine efficacy showed similar efficacy point estimates. The vaccine efficacy against RSV-associated LRTD was 66.7% (95% CI [41.8, 82.0]) for participants with at least one comorbidity of interest. The vaccine efficacy against RSV-associated LRTD was 65.4% (95% CI [40.4, 80.9]) in participants 60-69 years of age and 74.9% (95% CI [48.4, 89.2]) in participants 70-79 years of age. The vaccine efficacy in the subgroup of participants 80 years of age and older cannot be concluded due to the low number of total cases accrued (4 cases in the Arexvy group and 10 cases in the placebo group).
Amongst 55 RSV-LRTD cases (7 cases in the Arexvy group and 48 in the placebo group) with at least 2 lower respiratory signs or preventing everyday activities, 5 cases of severe RSV-LRTD requiring oxygen supplementation occurred in the placebo group, while there was 1 case in the Arexvy group.
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 according to their medical history. Sub-cohort 1 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. Sub-cohort 2 consisted of participants without pre-defined, stable, chronic medical conditions (Arexvy, N=383; placebo, N=192). Cohort 2 consisted of participants 60 years of age and older (Arexvy, N=381).
The primary immunogenicity objective was to demonstrate non-inferiority of the humoral immune response (in terms of RSV-A and RSV-B neutralizing titers) following the administration of Arexvy at 1-month post-vaccination in participants 50-59 years of age with pre-defined, stable, chronic medical conditions leading to an increased risk for RSV disease, compared to participants 60 years of age and older.
The prespecified criteria for non-inferiority of the immune responses were defined as the 2-sided 95% CI upper limits (UL) on the group geometric mean titer (GMT) ratios ≤1.50 and the UL of the 2-sided 95% CIs on the Seroresponse Rate (SRR) difference ≤10% for the RSV-A and RSV-B neutralizing titers in participants 60 years of age and older relative to participants 50 through 59 years of age with pre-defined, stable, chronic medical conditions leading to an increased risk for RSV disease. (See Table 2.)
Click on icon to see table/diagram/imageThe non-inferiority criteria of the immune responses for the RSV-A and RSV-B neutralizing 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 which 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 Dosage & Administration for information on paediatric use).
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.
Reproductive and developmental studies with an unadjuvanted RSVPreF3 vaccine as well as results from a study with Arexvy in rabbits did not reveal vaccine-related effects on female fertility, pregnancy, or embryo-foetal or offspring development.
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