Arexvy - GlaxoSmithKline Biologicals SA

After reconstitution, a single dose of AREXVY is either 0.5 mL (vial and vial presentation) or approximately 0.5 mL (vial and prefilled syringe presentation) [see Dosage and Administration (2.2)].

AREXVY is supplied in two presentations as follows:

Vial and Vial Presentation

AREXVY is supplied in two vials that must be combined prior to administration. Prepare AREXVY by reconstituting the Lyophilized Antigen Component (a sterile white powder) with the accompanying Adjuvant Suspension Component (an opalescent, colorless to pale brownish sterile liquid), as described in the instructions below. Use only the supplied Adjuvant Suspension Component for reconstitution.

Figure 1	Figure 2	Figure 3	Figure 4
Figure 1. Cleanse both vial stoppers. Using a sterile needle and sterile syringe, withdraw the entire contents of the vial containing the Adjuvant Suspension Component (liquid) by slightly tilting the vial. Vial 1 of 2.	Figure 2. Slowly transfer entire contents of syringe into the Lyophilized Antigen Component vial (powder). Vial 2 of 2.	Figure 3. Gently swirl the vial until powder is completely dissolved. Do not shake vigorously.	Figure 4. After reconstitution, withdraw 0.5 mL from the vial containing the reconstituted vaccine and administer intramuscularly.

Vial and Prefilled Syringe Presentation

AREXVY is supplied in a vial of Lyophilized Antigen Component and a prefilled syringe of Adjuvant Suspension Component that must be combined prior to administration. Prepare AREXVY by reconstituting the Lyophilized Antigen Component (a sterile white powder) with the accompanying Adjuvant Suspension Component (an opalescent, colorless to pale brownish sterile liquid), as described in the instructions below. Use only the supplied Adjuvant Suspension Component for reconstitution.

Figure 1	Figure 2	Figure 3	Figure 4
Figure 1. Hold the ungraduated prefilled syringe of Adjuvant Suspension Component by the barrel and unscrew the syringe cap by twisting it counterclockwise. Attach a sterile needle by gently connecting the needle hub into the Luer Lock Adaptor (LLA) and rotate a quarter turn clockwise until you feel it lock.	Figure 2. Cleanse the Lyophilized Antigen Component vial stopper. Slowly transfer the entire contents of the prefilled syringe into the vial containing the Lyophilized Antigen Component.	Figure 3. Gently swirl the vial until the powder is completely dissolved. Do not shake vigorously.	Figure 4. After reconstitution, withdraw the entire contents of approximately 0.5 mL from the vial containing the reconstituted vaccine into the same syringe and administer intramuscularly.

For intramuscular use.

After reconstitution, AREXVY is an opalescent, colorless to pale brownish liquid. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, AREXVY should not be administered.

After reconstitution, administer AREXVY immediately or store protected from light in the refrigerator between 2°C and 8°C (36°F to 46°F) or at room temperature [up to 25°C (77°F)] and use within 4 hours. Discard reconstituted vaccine if not used within 4 hours.

The results of a postmarketing observational study suggest an increased risk of Guillain-Barré syndrome during the 42 days following vaccination with AREXVY [see Adverse Reactions (6.2)].

Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following administration of AREXVY.

Syncope (fainting) may occur in association with administration of injectable vaccines, including AREXVY. Procedures should be in place to avoid injury from fainting.

Immunocompromised persons, including those receiving immunosuppressive therapy, may have a diminished immune response to AREXVY. The safety and immunogenicity of AREXVY have been assessed in 261 solid organ transplant recipients [see Use in Specific Populations (8.6)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Individuals 60 Years of Age and Older

The safety of AREXVY was evaluated in 17,879 vaccine recipients.

Study 1 is a placebo‑controlled, Phase 3 clinical study conducted in Europe, North America, Asia, and the Southern Hemisphere (South Africa, Australia, and New Zealand), involving 24,966 participants, 60 years of age and older, who received AREXVY (N = 12,467) or saline placebo (N = 12,499). Study 2 is a non–placebo-controlled, open‑label, Phase 3 clinical study conducted in Europe, North America, and Asia, involving 1,653 participants, 60 years of age and older, who received AREXVY. Study 3 is a non–placebo-controlled, open‑label, Phase 3 clinical study conducted in New Zealand, Panama, and South Africa, involving participants 60 years of age and older who received 1 dose of AREXVY and FLUARIX QUADRIVALENT concomitantly (N = 442) or sequentially (N = 443). Study 5 is a non–placebo-controlled, open‑label, clinical study conducted in the United States involving participants 65 years of age and older who received 1 dose of AREXVY and FLUZONE HIGH DOSE QUADRIVALENT (influenza vaccine, high dose; manufactured by Sanofi Pasteur, Inc.) concomitantly (N = 516) or sequentially (N = 513). Study 6 is a non–placebo-controlled, open‑label, clinical study conducted in Belgium, Finland, France, Spain, and the United Kingdom involving participants 65 years of age and older who received 1 dose of AREXVY and FLUAD QUADRIVALENT (influenza vaccine, adjuvanted; manufactured by Seqirus, Inc.) concomitantly (N = 523) or sequentially (N = 522).

At the time of vaccination in study 1, the median age of the population was 69.0 years; 13,943 (55.8%) participants were 60 to 69 years of age, 8,978 (36.0%) participants were 70 to 79 years of age, and 2,045 (8.2%) participants were 80 years of age and older. The majority of participants were White (79.4%), followed by Black (8.7%), Asian (7.6%), and other racial/ethnic groups (4.3%); 5.5% were of Hispanic or Latino ethnicity; 51.7% were female. In study 2, the median age of the population at the time of vaccination was 69.0 years; 820 (49.6%) participants were 60 to 69 years of age, 621 (37.6%) participants were 70 to 79 years of age, and 212 (12.8%) participants were 80 years of age and older. In study 2, the majority of participants were White (67.8%), followed by Asian (30.0%), Black (2.0%), and other racial/ethnic groups (0.2%); 1.9% were of Hispanic or Latino ethnicity; 54.6% were female. In study 3, the median age of the population at the time of the vaccination was 67.0 years; 519 (58.6%) participants were 60 to 69 years of age, 288 (32.5%) participants were 70 to 79 years of age, and 78 (8.8%) participants were 80 years of age and older, respectively. In study 3, the majority of the participants were of mixed race (50.3%), followed by White (30.7%), and Black (16.0%); 34.7% were of Hispanic or Latino ethnicity; 51.5% were female. In study 5, the median age of the population was 70 years. The majority of the participants were White (68.7%), followed by other racial groups (15.8%), Black (13.6%), American Indian or Alaskan Native (1.0%), and Asian (0.8%); 32.1% were of Hispanic or Latino ethnicity; 49.6% were female. In study 6, the median age of the population was 71 years. The majority of the participants were White (99.3%), followed by American Indian or Alaska Native (0.3%), Unknown Race (0.1%), Black (0.1%), Asian (0.1%), and Mixed Race (0.1%); 1.8% were of Hispanic or Latino ethnicity; 49.3% were female.

Safety Data from Study 1

Solicited Adverse Reactions: In study 1, a subset of study participants (solicited safety set) was monitored for solicited adverse reactions using standardized paper diary cards during the 4 days (i.e., day of vaccination and the next 3 days) following a dose of AREXVY or placebo; 879 participants received AREXVY and 878 participants received placebo. The other study participants did not prospectively record solicited reactions on a diary card but may have reported them as unsolicited adverse reactions.

The reported frequencies of specific solicited local (administration site) and systemic adverse reactions (per participant) are presented in Table 2.

In the solicited safety set, the local administration site adverse reactions reported with AREXVY had a median duration of 2 days, and the systemic adverse reactions reported with AREXVY had a median duration ranging between 1 and 2 days.

Unsolicited Adverse Events: In all participants from study 1, unsolicited adverse events were monitored using paper diary cards during the 30-day period following vaccination (day of vaccination and the next 29 days).

Among participants in the solicited safety set, (AREXVY, N = 879 or placebo, N = 878), unsolicited adverse events occurring within 30 days after vaccination were reported in 14.9% and 14.6% of participants who received AREXVY and placebo, respectively.

In the exposed set, 24,966 participants, 60 years of age and older, received at least 1 dose of AREXVY (N = 12,467) or placebo (N = 12,499). Unsolicited adverse events occurring within 30 days of vaccination were reported in 33.0% and 17.8% of participants, respectively. The higher frequency of reported unsolicited adverse events among participants who received AREXVY, compared to participants who received placebo, was primarily attributed to events that are consistent with adverse reactions solicited among participants in the reactogenicity subset. Within 30 days after vaccination, atrial fibrillation was reported in 10 participants who received AREXVY and 4 participants who received placebo (of which 7 events in AREXVY arm and 1 event in placebo arm were serious); the onset of symptoms ranged from 1 to 30 days postvaccination. The currently available information on the atrial fibrillation is insufficient to determine a causal relationship to the vaccine. There were no other notable patterns or numerical imbalances between groups for specific categories of unsolicited adverse events.

Serious Adverse Events: In study 1, participants were monitored for all serious adverse events (SAEs) that occurred during the 6‑month period following administration of AREXVY (N = 12,467) or placebo (N = 12,499).

SAEs with onset within 6 months following vaccination were reported at similar rates in participants who received AREXVY (4.2%) or placebo (4.0%). Serious events of atrial fibrillation were reported in 13 participants who received AREXVY and 15 participants who received placebo within 6 months after vaccination.

Deaths: In study 1, with a median follow-up time of 12.2 months postvaccination, adverse events leading to death were reported for 110 participants (0.9%) who received a single dose of AREXVY (N = 12,469) and for 114 participants (0.9%) who received placebo (N = 12,503). Based on available information, there is no evidence of causal relationship to AREXVY. Causes of death among participants were consistent with those generally reported in adult and elderly populations.

Potential Immune‑Mediated Diseases: In study 1, participants were monitored for all potential immune‑mediated diseases (pIMDs) that occurred during the 6‑month period following administration of AREXVY (N = 12,467) or placebo (N = 12,499).

New onset pIMDs or exacerbation of existing pIMDs within 6 months following vaccination were reported for 0.3% of participants who received AREXVY and 0.3% of participants who received placebo. There were no notable imbalances between study groups in individual pIMDs reported.

Serious Adverse Events Reported from Other Studies

Study 2: Guillain-Barré syndrome beginning 9 days after AREXVY vaccination was reported in a participant enrolled in a study site in Japan.

Study 3: Acute disseminated encephalomyelitis (ADEM) was reported in 2 participants enrolled in a study site in South Africa; the onset of the symptoms was 7 and 22 days postvaccination, respectively. One event was fatal and the other non-fatal. These participants received AREXVY concomitantly with FLUARIX QUADRIVALENT. For both events, magnetic resonance imaging and cerebrospinal fluid analyses were not performed.

Individuals 50 through 59 Years of Age

Study 4 was a Phase 3, observer‑blind, randomized, placebo‑controlled study conducted in Argentina, Canada, Germany, Japan, the Netherlands, Poland, Spain, and the U.S., in participants 50 through 59 years of age (N = 769 AREXVY; N = 383 saline placebo), including a subset of participants with stable chronic medical conditions associated with an increased risk for LRTD caused by RSV defined as chronic pulmonary disease, chronic cardiovascular disease, diabetes, chronic kidney or liver disease (N = 386 AREXVY; N = 191 saline placebo). The study also enrolled participants 60 years of age and older (N = 381 AREXVY) [see Clinical Studies (14.2)].

At the time of vaccination in study 4, the median age was 57 years for the entire study population and 55 years for the age group 50 through 59 years. The racial/ethnic and sex distribution of study participants were similar in the two age groups. The majority of participants were White (83.8%), followed by Asian (11.2%), Black (3.3%), and other racial/ethnic groups (1.7%); 14.3% were of Hispanic or Latino ethnicity; 52.1% were female.

In study 4, all participants were monitored for solicited adverse reactions during the 4 days following vaccination (i.e., day of vaccination and the next 3 days) and for unsolicited adverse events, during the 30-day period following vaccination (day of vaccination and the next 29 days), using standardized paper diary cards. Participants were monitored for all SAEs and for all pIMDs (serious and non-serious cases) that occurred during the 6-month period following vaccination. Among participants, 99.2% have completed at least 6 months of follow-up following vaccination.

Solicited Adverse Reactions: The reported frequencies of specific solicited, local (administration site), and systemic adverse reactions among participants 50 through 59 years of age are presented in Table 3.

The rates of solicited local and systemic adverse reactions (Table 3) were similar in participants 50 through 59 years of age either with or without pre-defined, stable, chronic medical conditions associated with an increased risk for LRTD caused by RSV.

Overall, the median duration of solicited local adverse reactions and solicited systemic adverse reactions after AREXVY vaccination was 2-3 days and 1-2 days, respectively.

Unsolicited Adverse Events: Unsolicited adverse events within 30 days after vaccination were reported in 13.8% of participants, 50 through 59 years of age, who received AREXVY (N = 769) compared to 12.0% of participants who received placebo (N = 383). Within 30 days after vaccination, there were no cases of atrial fibrillation reported in participants 50 through 59 years of age.

Serious Adverse Events: In study 4, participants were monitored for all SAEs that occurred during the 6-month period following administration of AREXVY (N = 769) or placebo (N = 383). Among participants 50 through 59 years of age, SAEs with onset within 6 months postvaccination were reported in 2.3% of those who received AREXVY and 2.1% of those who received placebo.

Deaths: Among participants 50 through 59 years of age, adverse events leading to death within 12 months after vaccination were reported for 4 (0.5%) participants who received AREXVY (N = 769) and 1 (0.3%) participant who received placebo (N = 383). None of these deaths were considered causally related to AREXVY.

Potential Immune-Mediated Diseases: In study 4, participants were monitored for all pIMDs that occurred during the 6-month period following administration of AREXVY (N = 769) or placebo (N = 383). Among participants 50 through 59 years of age, new onset pIMDs or exacerbation of existing pIMDs with onset within 6 months postvaccination were reported in 0.5% of those who received AREXVY and 0.3% of those who received placebo. There were no notable imbalances between study groups in individual pIMDs reported.

Individuals 18 through 49 Years of Age

Study 7 was an open‑label Phase 3 study conducted in Australia, Canada, Germany, Japan, South Africa and the U.S., in participants 18 through 49 years of age with pre-specified, stable, chronic medical conditions leading to an increased risk for LRTD caused by RSV defined as chronic pulmonary disease, chronic cardiovascular disease, diabetes, chronic kidney or liver disease, or neurological or neuromuscular disease (N = 1,029). The study also enrolled participants 60 years of age and older (N = 429). All study participants received 1 dose of AREXVY [see Clinical Studies (14.2)].

At the time of vaccination in study 7, the median age was 40 years for the age group 18 through 49 years and 45 years for the entire study population. The racial/ethnic and sex distribution of study participants were similar in the two age groups. The majority of participants were White (57.0%), followed by Black (21.4%), Asian (11.9%), and other racial/ethnic groups (9.0%); 10.4% were of Hispanic or Latino ethnicity; 55.8% were female.

In study 7, all participants were monitored for solicited adverse reactions during the 4 days following vaccination (i.e., day of vaccination and the next 3 days), using standardized electronic diary (e‑diary) or as reported to an investigator. The unsolicited adverse events were collected during the 30‑day period following vaccination (i.e., day of vaccination and the next 29 days). Participants were monitored for all SAEs and for all pIMDs (serious and non‑serious cases) that occurred during the 6‑month period following vaccination. Among participants, 97.5% completed the study at month 6.

Solicited Adverse Reactions: The reported frequencies of specific solicited, local (administration site), and systemic adverse reactions among participants 18 through 49 years of age are presented in Table 4.

Overall, the median duration of solicited local adverse reactions and solicited systemic adverse reactions after AREXVY vaccination was 2‑3 days and 1‑2 days, respectively.

Unsolicited Adverse Events: Unsolicited adverse events within 30 days after vaccination were reported in 18.5% of participants, 18 through 49 years of age, who received AREXVY (N = 1029). Within 30 days after vaccination, there was 1 case of non‑serious atrial fibrillation reported in a 45-year old participant with an onset of 6 days postvaccination. The participant had obesity (BMI ≥ 30kg/m²), had a medical history of paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, hypercholesterolemia, insulin resistance and obstructive sleep apnea. The event did not result in changes to medication regimen taken for atrial fibrillation prior to study vaccination, was self-limited and resolved spontaneously 4 days after onset. The currently available information on atrial fibrillation is insufficient to determine a causal relationship to the vaccine.

Serious Adverse Events: In study 7, participants were monitored for all SAEs that occurred during the 6‑month period following the administration of AREXVY. Among participants 18 through 49 years of age (N = 1029), no SAEs related to vaccination with AREXVY with onset within 6 months postvaccination were reported.

Potential Immune-Mediated Diseases: In study 7, participants were monitored for all pIMDs that occurred during the 6‑month period following administration of AREXVY. Among participants 18 through 49 years of age (N = 1029), new onset pIMDs or exacerbation of existing pIMDs with onset within 6 months postvaccination were reported in 0.2% of those who received AREXVY. One non-serious case of hematoma that initially developed at an insulin injection site prior to vaccination and subsequently exacerbated as multiple hematomas at other body sites was reported in a 31-year old participant with an onset of 14 days postvaccination. The event resolved spontaneously 217 days after onset.

The following adverse reactions have been identified from spontaneous reports during postmarketing use of AREXVY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.

Nervous System Disorders

Guillain-Barré Syndrome

Postmarketing Observational Study of the Risk of Guillain-Barré Syndrome following Vaccination with AREXVY

The association between vaccination with AREXVY and Guillain-Barré syndrome (GBS) was evaluated among Medicare beneficiaries 65 years of age and older. Using Medicare claims data, between May 2023 through July 2024, vaccinations with AREXVY were identified through Current Procedural Terminology (CPT)/Healthcare Common Procedure Coding System (HCPCS) codes and National Drug Codes, and potential cases of hospitalized GBS among recipients of AREXVY were identified through International Classification of Diseases (ICD) codes. GBS diagnoses in claims data were confirmed by medical record review when available.

The risk of GBS following vaccination with AREXVY was assessed in self-controlled case series analyses using a risk window of 1 to 42 days postvaccination and a control window of 43 to 90 days postvaccination. The analyses of all GBS cases based on claims data suggest an increased risk of GBS during the 42 days following vaccination with AREXVY, with an incidence rate ratio (GBS cases in the risk window/control window) of 2.46 (95% CI 1.19, 5.08) and an estimated 7 excess cases of GBS per million doses administered to individuals 65 years of age and older. The background risk of GBS in a study population influences the excess GBS case estimate and may differ between studies, precluding direct comparison to excess GBS case estimates from other vaccine studies or populations.

The analyses of GBS diagnoses in claims data were supported by analyses of GBS cases confirmed by medical record review and by analyses of GBS cases in individuals who received AREXVY alone, without other concomitantly administered vaccines. While the results of this observational study suggest an increased risk of GBS with AREXVY, available evidence is insufficient to establish a causal relationship.

Risk Summary

All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There are no data from clinical trials on the use of AREXVY in pregnant individuals. In a clinical study that enrolled pregnant individuals who received an investigational unadjuvanted RSV vaccine that contained the same RSVPreF3 antigen as AREXVY, an increase in preterm births was observed compared with pregnant individuals who received placebo (sucrose reconstituted with saline). This observation raises uncertainty about the use of AREXVY in pregnant individuals [see Indications and Usage (1)].

A developmental and reproductive toxicology study was performed in female rabbits administered AREXVY prior to mating and during gestation (0.5 mL at each occasion). This study revealed no adverse effects on female fertility, embryo‑fetal, pre‑weaning and post‑natal development (see Data ).

Available data are insufficient to determine a causal relationship between preterm birth and AREXVY.

Data

Human Data: There are no data from clinical trials on the use of AREXVY in pregnant individuals. In a randomized controlled clinical trial that enrolled pregnant individuals in a 2:1 ratio, 3,557 received an investigational unadjuvanted RSV vaccine that contained the same RSVPreF3 antigen as AREXVY and 1,771 received placebo (sucrose reconstituted with saline) at 24 to 34 weeks gestation. Numerical imbalances between the vaccine and placebo groups were observed for preterm births (6.8% and 4.9%, respectively) and neonatal deaths (0.4% and 0.2%, respectively). The observed numerical imbalance in neonatal deaths was not considered as an independent safety signal but as a consequence of the identified risk of preterm birth (0.2% and 0 in the vaccine and placebo groups in preterm infants, respectively).

Animal Data: In a developmental toxicity study, female rabbits were administered AREXVY by intramuscular injection 28 and 14 days prior to mating, on gestation Days 3, 9, 16, and 24, and on lactation Day 7. The total dose was 0.5 mL on each occasion (a single human dose of AREXVY is 0.5 mL). No adverse effects on female fertility or pre‑weaning development up to post‑natal Day 35 were observed.

Risk Summary

It is not known whether AREXVY is excreted in human milk. No human or animal data are available to assess the effects of AREXVY on the breastfed infant or on milk production/excretion.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AREXVY and any potential adverse effects on the breastfed child from AREXVY or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.

Evidence from an animal model strongly suggests that AREXVY would be unsafe in individuals younger than 2 years of age because of an increased risk of enhanced respiratory disease. Safety and effectiveness in individuals 2 years through 17 years of age have not been established.

Of the total number of participants (N = 24,966) who received AREXVY or placebo in study 1, 13,943 (55.8%) were 60 to 69 years of age, 8,978 (36.0%) were 70 to 79 years of age, and 2,045 (8.2%) were 80 years of age and older [see Adverse Reactions (6.1), Use in Specific Populations (8.6), and Clinical Studies (14.1)].

In study 8 (NCT05921903), an open-label, Phase 2b, partially randomized, controlled study, solid organ transplant (SOT) recipients (kidney or lung) 18 years of age and older were randomized to receive either one dose of AREXVY (N = 131) or two doses of AREXVY (an unapproved dosing regimen) with a second dose administered 30-60 days later (N = 130 Dose 1, N = 121 Dose 2). A non-randomized cohort of non-immunocompromised participants 50 years of age and older, including those with chronic stable medical conditions, received one dose of AREXVY (N = 125). Among SOT recipients (N = 261), the mean age was 61.8 years; 39.8% were female; and 64.4% were White, 7.3% were Black or African American, 26.1% were Asian, and 0.8% were other racial/ethnic groups; 6.5% were of Hispanic or Latino ethnicity. Of SOT recipients, 76.6% were on immunosuppressive regimens including mycophenolate, and 23.4% were on immunosuppressive regimens without mycophenolate.

Solicited local and systemic reactions that occurred within 7 days following study vaccination were collected. Unsolicited adverse events were collected for 1 month after each dose of study vaccination, and serious adverse events were collected for at least 13 months after last dose of study vaccination in SOT recipients.

The solicited reactogenicity profile in SOT recipients was similar to those observed in other studies [see Adverse Reactions (6.1)]. In study 8, following one dose of AREXVY, solicited local adverse reactions were reported in 73.3% of SOT recipients compared with 76.8% of non-immunocompromised adults. Following two doses of AREXVY, solicited local adverse reactions were reported in 71.9% of SOT recipients after the first dose and 68.6% after the second dose. Pain at the injection site was the most frequently reported solicited local reaction in SOT recipients (72.2% and 67.8% of participants after one dose or after two doses, respectively) and in non-immunocompromised adults (76.0%). Following one dose of AREXVY, solicited systemic adverse reactions were reported in 55.0% of SOT recipients compared with 59.2% of non-immunocompromised adults. Following two doses of AREXVY, solicited systemic adverse reactions were reported in 51.6% of SOT recipients after the first dose and 54.5% after the second dose. Fatigue was the most frequently reported solicited systemic adverse reaction in SOT recipients (33.2% and 38.8% of participants who received one or two doses, respectively).

Neutralizing antibody responses against RSV-A and RSV-B at 30-60 days after vaccination in study 8 were assessed as seroresponse rate (SRR), defined as achieving a ≥4-fold rise in neutralizing titers from baseline, and geometric mean titer (GMT). In non-immunocompromised adults, the SRR was 82.1% (95% CI [73.9%, 88.5%]) and 87.2% (95% CI [79.7%, 92.6%]) for RSV-A and RSV-B, respectively, following one dose of AREXVY. The GMT was 6,881.3 (95% CI [5,976.2, 7,923.6]) and 9,125.2 (95% CI [7,781.9, 10,700.5]) for RSV-A and RSV-B, respectively, following one dose of AREXVY.

Among SOT recipients on immunosuppressive regimen with mycophenolate: Following one dose of AREXVY, the SRR was 47.2% (95% CI [36.5%, 58.1%]) and 48.3% (95% CI [37.6%, 59.2%]) for RSV-A and RSV-B, respectively. Following two doses of AREXVY, the SRR was 62.1% (95% CI [51.0%, 72.3%]) and 60.9% (95% CI [49.9%, 71.2%]) for RSV-A and RSV-B, respectively. The GMT was 3,601.8 (95% CI [2,671.9, 4,855.4]) and 4,041.4 (95% CI [3,012.1, 5,422.3]) for RSV-A and RSV-B, respectively, following one dose of AREXVY. Following two doses of AREXVY, the GMT was 4,960.3 (95% CI [3,778.9, 6,511.0]) and 5,274.4 (95% CI [4,062.3, 6,848.1]) for RSV-A and RSV-B, respectively.

Among SOT recipients on immunosuppressive regimen without mycophenolate: Following one dose of AREXVY, the SRR was 75.0% (95% CI [53.3%, 90.2%]) and 70.8% (95% CI [48.9%, 87.4%]) for RSV-A and RSV-B, respectively. Following two doses of AREXVY, the SRR was 78.3% (95% CI [56.3%, 92.5%]) for both RSV-A and RSV-B. The GMT was 7,255.2 (95% CI [4,667.7, 11,277.0]) and 9,468.3 (95% CI [5,899.8, 15,195.3]) for RSV-A and RSV-B, respectively, following one dose of AREXVY. Following two doses of AREXVY, the GMT was 7,327.2 (95% CI [4,811.0, 11,159.4]) and 8,487.5 (95% CI [5,736.0, 12,558.8]) for RSV-A and RSV-B, respectively.

All SOT recipients at 12 months postvaccination: The GMT in all SOT recipients (regardless of type of immunosuppressive regimen) was 1,773.4 (95% CI [1,486.2, 2,116.2]) and 2,206.7 (95% CI [1,811.3, 2,688.5]), respectively, for RSV-A and RSV-B following one dose of AREXVY compared with 2,517.4 (95% CI [2,039.3, 3,107.5]) and 2,886.5 (95% CI [2,368.0, 3,518.4]), respectively, for RSV-A and RSV-B following two doses of AREXVY. The 12-month postvaccination GMTs in non-immunocompromised adults was 2,243.6 (95% CI [1,925.0, 2,614.9]) and 2,665.1 (95% CI [2,310.9, 3,073.5]), respectively, for RSV-A and RSV-B.

The data from this study do not establish the effectiveness of AREXVY in immunocompromised individuals.

AREXVY induces an immune response against RSVpreF3 that protects against LRTD caused by RSV.

AREXVY has not been evaluated for carcinogenic or mutagenic potential or for impairment of male fertility.

Efficacy of AREXVY against RSV‑associated LRTD in individuals 60 years of age and older was evaluated for up to 3 RSV seasons in study 1, a Phase 3, randomized, placebo‑controlled, observer‑blind clinical study conducted in 17 countries from Northern and Southern Hemispheres.

The study excluded participants who were immunocompromised. Participants with pre‑existing, chronic, stable disease such as diabetes, hypertension, or cardiac disease were allowed to participate in the study if considered by the investigator as medically stable at the time of vaccination.

The primary population for efficacy analysis (referred to as the modified exposed set), included individuals 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.

The primary efficacy analysis over the first RSV season included 24,960 participants randomized equally to receive 1 dose of AREXVY (N = 12,466) or placebo (N = 12,494).

The efficacy analysis up to the end of the second RSV season included participants who received a single dose of AREXVY before Season 1 (N = 12,469); due to valid informed consent obtained from some participants initially excluded from the primary efficacy analysis, there is a higher number of participants in the end of Season 2 analysis. Pre‑Season 2, participants who received AREXVY were re‑randomized to receive placebo (N = 4,991) or a second dose of AREXVY (N = 4,966). Participants who received placebo before Season 1 (N = 12,498) received a second dose of placebo before Season 2 (N = 10,031). The efficacy analysis up to the end of the third RSV season included participants who received a single dose of AREXVY before Season 1 (N = 12,468); duplicate data from one participant was excluded from end of Season 3 analysis.

The participants were followed up to the end of the third RSV season (median follow‑up time 30.6 months).

Among study 1 participants in the modified exposed set for the analysis of efficacy over the first RSV season, 51.7% were female; 79.4% were White, 8.7% were Black, 7.6% were Asian, and 4.3% were of other racial/ethnic groups including American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander; 5.5% were of Hispanic or Latino ethnicity. The median age of participants was 69.0 years.

At baseline, 39.3% of participants had at least one comorbidity of interest; 19.7% of participants had an underlying cardiorespiratory condition (chronic obstructive pulmonary disease, asthma, any chronic respiratory/pulmonary disease, or chronic heart failure) and 25.8% of participants had endocrine and metabolic conditions (diabetes, advanced liver or renal disease). Among participants in the modified exposed set for the analysis of efficacy over 2 and over 3 RSV seasons, demographic and baseline characteristics were similar to those in the modified exposed set for the analysis of efficacy over the first RSV season.

In study 1, confirmed RSV cases were determined by quantitative Reverse Transcription Polymerase Chain Reaction (qRT‑PCR) on a nasopharyngeal swab during all ARI episodes. ARI was defined by the presence of at least 2 respiratory symptoms/signs for at least 24 hours (nasal congestion, sore throat, lower respiratory symptoms/signs, as described below), or at least 1 respiratory symptom/sign plus 1 systemic symptom/sign (fever or feverishness, fatigue, body aches, headache, decreased appetite) for at least 24 hours. 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%), need for oxygen supplementation.

In study 1, a severe RSV-associated LRTD was defined as an RT-PCR confirmed RSV-associated LRTD with at least 2 lower respiratory signs, or preventing normal, everyday activities or requiring supportive therapy.

Efficacy against Respiratory Syncytial Virus-Associated Lower Respiratory Tract Disease over the First Respiratory Syncytial Virus Season

The primary objective was to demonstrate the efficacy of AREXVY in the prevention of a first episode of confirmed RSV-A and/or B associated LRTD during the first season.

Compared with placebo, AREXVY significantly reduced the risk of developing RSV-associated LRTD by 82.6% (96.95% CI [57.9, 94.1]) in participants 60 years of age and older, which met the pre-specified success criterion for the primary study objective (Table 5). The median duration of efficacy follow-up was 6.7 months.

Vaccine efficacy analyses by age subgroup and for participants with at least one comorbidity of interest are presented in Table 5.

The vaccine efficacy against RSV‑A–associated LRTD and RSV‑B–associated LRTD was 84.6% (95% CI [32.1, 98.3]) and 80.9% (95% CI [49.4, 94.3]), respectively.

Compared with placebo, AREXVY significantly reduced the risk of developing RSV-associated LRTD by 84.4% (95% CI [46.9, 97.0]) in participants 70 years of age and older.

Compared with placebo, AREXVY significantly reduced the risk of developing severe RSV-associated LRTD by 94.1% (95% CI [62.4, 99.9]) in participants 60 years of age and older. One case of severe RSV-associated LRTD in the group that received AREXVY and 17 cases in the group that received placebo were reported, amongst which 2 cases required supportive therapy i.e., oxygen supplementation.

Efficacy against Respiratory Syncytial Virus‑Associated Lower Respiratory Tract Disease over 2 and over 3 Respiratory Syncytial Virus Seasons

Participants 60 years of age and older who received 1 dose of AREXVY or placebo were followed over 3 RSV seasons (up to the end of the second and third seasons in the Northern Hemisphere), with a median follow‑up time of 17.8 months over 2 RSV seasons and 30.6 months over 3 RSV seasons. The vaccine efficacy against RSV‑associated LRTD over 2 RSV seasons was 67.2% (97.5% CI [48.2, 80.0]) and over 3 RSV seasons was 62.9% (97.5% CI [46.7, 74.8]).

The vaccine efficacy against RSV-A‑associated LRTD and RSV-B‑associated LRTD over 3 RSV seasons was 69.8% (97.5% CI [42.2, 85.7]) and 58.6% (97.5% CI [35.9, 74.1]), respectively.

Vaccine efficacy analyses by age subgroup and for participants with at least one comorbidity of interest are presented in Table 6.

In participants 70 years of age and older, over 2 RSV seasons and over 3 RSV seasons, the vaccine efficacy against RSV‑associated LRTD was 69.3% (95% CI [43.4, 84.6]) and 66.0% (95% CI [44.3, 80.2]), respectively.

The vaccine efficacy against severe RSV‑associated LRTD over 2 RSV seasons was 78.8% (95% CI [52.6, 92.0]) in participants 60 years of age and older (7 cases in participants who received 1 dose of AREXVY and 48 cases in participants who received placebo, amongst which supportive therapy (i.e., oxygen supplementation and positive airway pressure) was required for 1 case in participants who received 1 dose of AREXVY and 5 cases in participants who received placebo). The vaccine efficacy against severe RSV‑associated LRTD over 3 RSV seasons was 67.4% (95% CI [42.4, 82.7]) in participants 60 years of age and older (15 cases in participants who received 1 dose of AREXVY and 75 cases in participants who received placebo, amongst which supportive therapy (i.e., oxygen supplementation and positive airway pressure) was required for 2 cases in participants who received 1 dose of AREXVY and 5 cases in participants who received placebo).

Efficacy against Respiratory Syncytial Virus‑Associated Lower Respiratory Tract Disease over the Second Respiratory Syncytial Virus Season and over the Third Respiratory Syncytial Virus Season

The vaccine efficacy against RSV‑associated LRTD over the second RSV season with median follow‑up of 6.3 months was 56.1% (95% CI [28.2, 74.4]) in participants 60 years of age and older (20 cases among participants who received 1 dose of AREXVY and 91 cases among participants who received placebo).

The vaccine efficacy against RSV‑associated LRTD over the third RSV season with median follow‑up of 7 months was 48.0% (95% CI [8.7, 72.0]) in participants 60 years of age and older (16 cases among participants who received 1 dose of AREXVY and 61 cases among participants who received placebo).

In study 4, individuals 50 through 59 years of age with an increased risk of LRTD caused by RSV due to certain chronic medical conditions (chronic pulmonary disease, chronic cardiovascular disease, diabetes, chronic kidney or liver disease) were randomized to receive AREXVY (N = 386) or saline placebo (N = 191). A comparator group of individuals 60 years and older also received AREXVY (N = 381) [see Adverse Reactions (6.1)].

In study 7, individuals 18 through 49 years of age with an increased risk of LRTD caused by RSV due to certain chronic medical conditions (participants may have reported more than 1 condition) were enrolled to receive AREXVY (N = 1,029; 426 of whom were part of the immunogenicity subset). These conditions included cardiopulmonary disorders (55.0%), diabetes mellitus (48.9%), chronic kidney disease (2.9%), chronic liver disease (6.2%), and neurologic or neuromuscular conditions (20.5%). A comparator group of individuals 60 years and older also received AREXVY (N = 429). All study participants received 1 dose of AREXVY [see Adverse Reactions (6.1)].

In both study 4 and study 7, effectiveness of AREXVY in individuals 50 through 59 years of age and individuals 18 through 49 years of age with chronic medical conditions was assessed by a comparison of RSV neutralizing antibody responses induced by AREXVY in these age groups to antibody responses of individuals 60 years of age and older. The neutralizing antibody responses to RSV‑A and RSV‑B subtypes in individuals 50 through 59 years of age and 18 through 49 years of age with chronic medical conditions met the criteria for immunobridging. The noninferiority criteria, as pre‑specified in the protocol, were met as the upper limit (UL) of the 2‑sided 95% CIs for the Geometric Mean Titer (GMT) ratios (GMT for individuals 60 years and older/GMT for individuals 50 through 59 years of age, and GMT for individuals 60 years and older/GMT for individuals 18 through 49 years of age) were ≤1.50 and the UL of the 2‑sided 95% CIs for seroresponse rate (SRR) differences (SRR for individuals 60 years and older minus SRR for individuals 50 through 59 years of age, and SRR for individuals 60 years and older minus SRR for individuals 18 through 49 years of age) were ≤10% for the RSV‑A and RSV‑B subtypes. For clarity, Table 7 presents the GMT ratio as GMT for individuals 50 through 59 years of age/GMT for individuals 60 years and older or GMT for individuals 18 through 49 years of age/GMT for individuals 60 years and older, for which the corresponding noninferiority criterion is a 2‑sided 95% CI lower limit (LL) ≥0.67. Similarly, Table 7 presents the SRR difference as SRR for individuals 50 through 59 years of age minus SRR for individuals 60 years and older or SRR for individuals 18 through 49 years of age minus SRR for individuals 60 years and older, for which the corresponding noninferiority criterion is a 2‑sided 95% CI LL ≥-10%.

Concomitant Administration with Influenza Vaccines

In 3 open‑label clinical studies, participants were randomized 1:1 to receive 1 dose of AREXVY administered either concomitantly at month 0 or sequentially 1 month apart (referred to as the control group) with FLUARIX QUADRIVALENT in study 3 (N = 885), FLUZONE HIGH DOSE QUADRIVALENT in study 5 (N = 1,029), or FLUAD QUADRIVALENT (N = 1,045) in study 6 [see Adverse Reactions (6)].

In studies 3 and 5, the prespecified criteria for noninferiority of the immune responses in the concomitant administration group versus the control group were met for the RSV‑A neutralizing titers (studies 3 and 5), the RSV‑B neutralizing titers (study 5), and for the haemagglutinin inhibition (HI) titers against influenza strains A/Hong Kong/H3N2, A/Victoria/H1N1, B/Phuket/Yamagata and B/Washington/Victoria (study 3) and influenza strains A/Victoria/H1N1, A/Darwin/H3N2, B/Austria/Victoria and B/Phuket/Yamagata (study 5). The prespecified criterion for noninferiority was an upper limit of the 2-sided 95% confidence interval on the GMT ratio (control group/concomitant group) ≤1.5, which corresponds to a lower limit of the 2-sided 95% confidence interval on the GMT ratio (concomitant group/control group) ≥0.67.

In study 6, the prespecified criteria for noninferiority of the immune responses in the concomitant administration group versus the control group were met for the RSV‑A neutralizing titers and for HI titers against 3 of 4 influenza vaccine strains (A/Victoria/H1N1, B/Austria/Victoria, and B/Phuket/Yamagata). The prespecified criterion for noninferiority was an upper limit of the 2-sided 95% confidence interval on the GMT ratio (control group/concomitant group) ≤1.5, which corresponds to a lower limit of the 2-sided 95% confidence interval on the GMT ratio (concomitant group/control group) ≥0.67. The noninferiority criterion was not met for HI titers against A/Darwin/H3N2 influenza strain, with the lower limit of the 95% CI of the GMT ratio of 0.65. In a post‑hoc descriptive analysis, the GMT ratio [concomitant group/control group] was 0.86 [2‑sided 95% CI (0.77, 0.97)] for RSV‑B neutralizing titers.

Adjuvant Suspension Component vials and prefilled syringes: Store refrigerated between 2°C and 8°C (36°F and 46°F). Store in the original package in order to protect vials and prefilled syringes from light. Do not freeze. Discard if the Adjuvant Suspension Component has been frozen.

Lyophilized Antigen Component vials: Store refrigerated between 2°C and 8°C (36°F and 46°F). Store in the original package in order to protect vials from light. Do not freeze. Discard if the Lyophilized Antigen Component has been frozen.

Unopened vaccine components in the original package may be kept for up to 7 days (cumulative excursion period) at temperatures between 8°C and 25°C (46°F to 77°F). However, keeping the vaccine components at temperatures between 8°C and 25°C (46°F to 77°F) are not recommendations for storage.

• Administer immediately or store in the refrigerator between 2°C and 8°C (36°F to 46°F) or at room temperature [up to 25°C (77°F)] for up to 4 hours prior to use.
• Protect reconstituted vaccine from light.
• Discard reconstituted vaccine if not used within 4 hours.
• Do not freeze. Discard if the vaccine has been frozen.