1.1 Immunization of Pregnant Individuals

ABRYSVO is a vaccine indicated for active immunization of pregnant individuals at 32 through 36 weeks gestational age for the prevention of lower respiratory tract disease (LRTD) and severe LRTD caused by respiratory syncytial virus (RSV) in infants from birth through 6 months of age.

1.2 Immunization of Individuals 60 Years of Age and Older

ABRYSVO is a vaccine indicated for active immunization for the prevention of LRTD caused by RSV in individuals 60 years of age and older.

2.1 Dose and Schedule

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

2.2 Presentations and Reconstitution

ABRYSVO is supplied in 2 presentations as follows:

Vial and Prefilled Syringe Presentation

The vial and prefilled syringe presentation is supplied in a kit that includes a vial of Lyophilized Antigen Component (a sterile white powder), a prefilled syringe containing the Sterile Water Diluent Component, and a vial adapter.

Vial and Vial Presentation

The vial and vial presentation is supplied in cartons that include vials of Lyophilized Antigen Component (a sterile white powder) and vials containing the Sterile Water Diluent Component.

For both presentations, reconstitute the Lyophilized Antigen Component with the accompanying Sterile Water Diluent Component to form ABRYSVO, as described in the instructions below.

Reconstitution Instructions for Vial and Prefilled Syringe Presentation

Step 1. Attachment of the vial adapter to the vial Remove the flip top cap from the vial of Lyophilized Antigen Component. Peel off the top cover from the vial adapter packaging. While keeping the vial adapter in its packaging, center the adapter over the vial’s stopper and attach to the vial with a straight downward push. Remove the packaging.	Step 2. Connection of the syringe to the vial adapter Hold the syringe of Sterile Water Diluent Component by the Luer lock adapter. Twist to remove the syringe cap. Connect the syringe to the vial adapter by turning the Luer lock.	Step 3. Reconstitution of the Lyophilized Antigen Component with the Sterile Water Diluent Component to form ABRYSVO Inject the entire contents of the syringe into the vial. Hold the plunger rod down and gently swirl the vial until the powder is completely dissolved (less than 1 minute). Do not shake.	Step 4. Withdrawal of ABRYSVO Invert the vial completely and slowly withdraw the entire contents into the syringe for an approximately 0.5 mL dose of ABRYSVO. Twist to disconnect the syringe from the vial adapter. Attach a sterile needle suitable for intramuscular injection.

Reconstitution Instructions for the Vial and Vial Presentation

Step 1. Withdrawal of the Sterile Water Diluent Using a sterile needle and sterile syringe, withdraw the entire contents of the vial containing the Sterile Water Diluent Component.	Step 2. Reconstitution of the Lyophilized Antigen Component with the Sterile Water Diluent Component to form ABRYSVO Inject the entire contents into the vial containing the Lyophilized Antigen Component (white powder). Gently swirl the vial in a circular motion until the powder is completely dissolved. Do not shake.		Step 3. Withdrawal of ABRYSVO Withdraw 0.5 mL from the vial containing the reconstituted vaccine.

2.3 Administration

For intramuscular injection

After reconstitution, ABRYSVO is a clear and colorless solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if either condition is present.

Administer ABRYSVO immediately or store at room temperature [15°C to 30°C (59°F to 86°F)] and use within 4 hours. Discard reconstituted vaccine if not used within 4 hours.

5.1 Potential Risk of Preterm Birth

A numerical imbalance in preterm births in ABRYSVO recipients was observed compared to placebo recipients in two clinical studies [see Adverse Reactions 6.1]. Available data are insufficient to establish or exclude a causal relationship between preterm birth and ABRYSVO. To avoid the potential risk of preterm birth with use of ABRYSVO before 32 weeks of gestation, administer ABRYSVO as indicated in pregnant individuals at 32 through 36 weeks gestational age. Pregnant individuals who were at increased risk of preterm birth were generally excluded from clinical studies of ABRYSVO.

5.2 Management of Acute Allergic Reactions

Appropriate medical treatment used to manage immediate allergic reactions must be immediately available in the event an anaphylactic reaction occurs following administration of ABRYSVO.

5.3 Syncope

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

5.4 Altered Immunocompetence

Immunocompromised individuals, including those receiving immunosuppressive therapy, may have a diminished immune response to ABRYSVO.

5.5 Limitations of Vaccine Effectiveness

Vaccination with ABRYSVO may not protect all vaccine recipients.

6.1 Clinical Trials Experience

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

Pregnant Individuals and Infants from Birth Through 6 Months of Age

The safety of ABRYSVO in maternal and infant participants was evaluated in two clinical studies in which approximately 4,000 maternal participants received a single dose of ABRYSVO.

Study 1 (NCT04424316) is an ongoing, Phase 3, randomized, double-blind, multicenter, placebo-controlled study to investigate the efficacy and safety of ABRYSVO administered to pregnant individuals ≤49 years of age with uncomplicated, singleton pregnancies, to protect their infants against RSV disease. Pregnant individuals with high-risk pregnancies were excluded from the study (BMI>40 kg/m2 prior to pregnancy, pregnancies resulting after in vitro fertilization, preeclampsia, eclampsia, uncontrolled gestational hypertension, placental abnormalities, polyhydramnios or oligohydramnios, significant bleeding or blood clotting disorder, unstable endocrine disorders including untreated disorders of glucose intolerance or thyroid disorders). Pregnant individuals with prior pregnancy complications (e.g., history of preterm birth ≤34 weeks gestation, prior stillbirth, neonatal death, previous infant with a known genetic disorder or significant congenital anomaly) could be included, based on the investigators’ judgment, but were generally not enrolled in the study. In this study with 1:1 randomization 3,682 participants received ABRYSVO and 3,675 received placebo (0.5 mL dose, containing the same buffer ingredients in the same quantities as in a single dose of ABRYSVO [see Description (11)]). Infants born in year 1 are to be followed for up to 24 months, and infants born in year 2 will be followed for up to 12 months to assess safety. At the time of data evaluation following a median of 8.9 months (range Day 1-23.8 months), 3,568 infants were born to the maternal participants in the ABRYSVO group and 3,558 in the placebo group, and of these, approximately 45.6% have been followed for 12 months. This multicenter study is being conducted in Argentina, Australia, Brazil, Canada, Chile, Denmark, Finland, Gambia, Japan, Republic of Korea, Mexico, Netherlands, New Zealand, Philippines, South Africa, Spain, Taiwan, and the US.

Demographic characteristics in Study 1 among participants who received ABRYSVO and those who received placebo were generally similar with regard to age, race, and ethnicity. Of the participants in the study, 65% were White, 20% were Black or African American, 13% were Asian, and 29% were Hispanic/Latino. The median maternal age at the time of study vaccination was 29 years (range 16 to 45 years in the ABRYSVO group, 14 to 47 years in the placebo group). The median gestational age at vaccination was 31 weeks and 2 days (range 24-36.9 weeks). ABRYSVO is approved for use for pregnant individuals at 32 through 36 weeks gestational age [see Indications and Usage (1.1)]. The median infant gestational age at birth was 39 weeks and 1 day (range 27 weeks and 3 days to 44 weeks and 2 days). Among the infants born to maternal participants 51% were male and 49% were female.

Study 2 (NCT04032093) was a Phase 2, randomized, placebo-controlled, observer-blinded study that investigated the safety of two dose levels (120 mcg and a higher dose) of ABRYSVO administered to pregnant individuals. ABRYSVO (120 mcg) was administered to 115 maternal participants, and 114 infants were born to these maternal participants. This study was conducted in the US, South Africa, Argentina, and Chile. Demographic characteristics among participants who received ABRYSVO and those who received placebo were generally similar with regard to age, race, and ethnicity. Of the participants in the study, 76% were White, 21% were Black or African American, and 28% were Hispanic/Latino. The median age of participants was 27 years (range 18-42 years). The median gestational age at vaccination was 30 weeks (range 24-36 weeks). ABRYSVO is approved for use for pregnant individuals at 32 through 36 weeks gestational age [see Indications and Usage (1.1)].

For all maternal participants in Study 1, solicited local reactions and systemic events were collected using electronic diaries for 7 days after study vaccination, adverse events for 1 month and obstetric complications, serious adverse events, and adverse events of special interest for the duration of the study. For infant participants, the collection period for nonserious adverse events was from birth to 1 month. Serious adverse events were monitored for at least 1 year for all infant participants and for up to 2 years for half of the infants in Study 1.

Solicited Local and Systemic Reactions in Study 1

The majority of solicited local and systemic reactions in maternal participants resolved within 2-3 days of onset. Severe local reactions were reported for 0.3% of maternal participants in the ABRYSVO group and none in the placebo group, and severe systemic reactions within 7 days after vaccination were reported by 2.3% of maternal participants in both groups.

Solicited local and systemic reactions reported within 7 days after vaccination in Study 1 are presented in Tables 1 and 2.

Unsolicited Adverse Events in Study 1

Unsolicited adverse events reported within 1 month after vaccination by maternal participants were 13.7% in the ABRYSVO group and 13.1% in the placebo group.

The most frequently reported unsolicited adverse events in maternal participants from vaccination through the 1-month follow-up visit were disorders of pregnancy, puerperium and perinatal conditions (7.0% for the ABRYSVO group versus 6.2% for the placebo group).

Serious Adverse Events in Study 1

In Study 1, serious adverse events in maternal participants were reported by 16.2% in the ABRYSVO group and 15.2% in the placebo group occurring any time during the study (see Table 3) with 4.2% serious adverse events in the ABRYSVO group and 3.7% in the placebo group occurring within 1 month after vaccination. Most of the serious adverse events in maternal participants were related to pregnancy complications and occurred after the 1 month period following vaccination.

Preterm Births in Study 1 and Study 2

A numerical imbalance in preterm births in ABRYSVO recipients compared to placebo recipients was observed in both Studies 1 and 2. In Study 2, preterm births occurred in 5.3% (6 out of 114) in the ABRYSVO group and 2.6% (3 out of 116) in the placebo group. In the subsequent Study 1, preterm birth events occurred in 5.7% [95% CI: 4.9, 6.5] (202 out of 3,568) in the ABRYSVO group and 4.7% [95% CI: 4.1, 5.5] (169 out of 3,558) in the placebo group. In infants born preterm, 83 infants in the ABRYSVO group and 80 infants in the placebo group remained hospitalized or were readmitted to the hospital in the neonatal period (up to 30 days after birth). Available data are insufficient to establish or exclude a causal relationship between preterm birth and ABRYSVO.

A numerical imbalance in preterm births was also observed in Study 1 among the subgroup of infants born to participants who were vaccinated at 32 through 36 weeks gestation, with 4.2% (68/1,631) in the ABRYSVO group and 3.7% (59/1,610) in the placebo group.

Adverse Reactions in Infants

In Study 1, adverse events in infants from birth to 1 month of age were observed in 37.1% in the ABRYSVO group compared to 34.5% in the placebo group. Low birth weight was observed in 5.1% of participants in the ABRYSVO group versus 4.4% in the placebo group, and neonatal jaundice was observed in 7.2% in the ABRYSVO group versus 6.7% in the placebo group.

Individuals 60 Years of Age and Older

The safety of ABRYSVO was evaluated in Study 3 (NCT05035212) in which 17,215 participants received ABRYSVO and 17,069 received placebo (0.5 mL dose, containing the same buffer ingredients in the same quantities as in a single dose of ABRYSVO [see Description (11)]). Study 3 is an ongoing, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of ABRYSVO in individuals 60 years of age and older. This study is being conducted in the US, Argentina, Japan, the Netherlands, Canada, South Africa, and Finland. Demographic characteristics among participants who received ABRYSVO and those who received placebo were generally similar with regard to age, sex, race, and ethnicity. Of the participants in the study, 51% were male and 78% were White, 13% were Black or African American, and 37% were Hispanic/Latino. The median age of participants was 67 years (range 59-97 years).

Solicited local and systemic reactions were collected using electronic diaries for 7 days after study vaccination in 7,169 participants (3,630 ABRYSVO participants and 3,539 placebo recipients) from a subset of sites. For all participants, unsolicited adverse events were collected for one month after study vaccination; serious adverse events (SAEs) are collected throughout study participation.

Solicited Local and Systemic Reactions in Study 3

Solicited local and systemic reactions reported within 7 days after vaccination in Study 3 are presented in Tables 4 and 5.

Solicited local and systemic reactions had a median duration of 1-2 days.

Unsolicited Adverse Events in Study 3

Unsolicited adverse events occurring within 1 month after vaccination were similar between groups, reported in 8.9% and 8.5% of participants who received ABRYSVO and placebo, respectively.

Within 30 days after vaccination, atrial fibrillation was reported in 10 vaccine recipients and 4 placebo recipients (of which 4 in the ABRYSVO group and 3 in the placebo group were serious adverse events); the onset of symptoms was 18 to 30 days post vaccination. The currently available information on 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 3

In Study 3, SAEs were reported by 2.3% of participants in both the ABRYSVO and placebo groups. Three participants in the ABRYSVO group had SAEs which were assessed as possibly related to study vaccination: Guillain-Barre Syndrome reported 7 days after vaccination, Miller Fisher Syndrome reported 8 days after vaccination, and hypersensitivity reported 8 hours after vaccination.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to ABRYSVO during pregnancy. Individuals who received ABRYSVO during pregnancy are encouraged to contact, or have their healthcare provider contact, 1-800-616-3791 to enroll in or obtain information about the registry.

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of ABRYSVO to prevent RSV LRTD and severe RSV LRTD in infants born to individuals vaccinated at younger than 10 years of age have not been established.

The safety and effectiveness of ABRYSVO to prevent RSV LRTD in non-pregnant individuals younger than 18 years of age via active immunization have not been established.

8.5 Geriatric Use

ABRYSVO is approved for use in individuals 60 years of age and older. In Study 3, of the 17,215 recipients who received ABRYSVO 62% (n=10,756) were aged 60-69 years of age, 32% (n=5,488) were 70-79 years of age and 6% (n=970) were ≥80 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

12.1 Mechanism of Action

Active Immunization

ABRYSVO induces an immune response against RSV pre F that protects against lower respiratory tract disease caused by RSV.

Passive Immunization

Antibodies to RSV antigens from individuals vaccinated in pregnancy are transferred transplacentally to protect infants younger than 6 months of age against LRTD and severe LRTD caused by RSV.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

ABRYSVO has not been evaluated for the potential to cause carcinogenicity, genotoxicity, or impairment of male fertility. A developmental toxicity study in female rabbits revealed no evidence of impaired female fertility after administration of a vaccine formulation containing two times the antigen content of a single human dose of ABRYSVO [see Use in Specific Populations (8.1)].

14.1 Study in Pregnant Individuals for Efficacy in Their Infants from Birth Through 6 Months of Age

Study 1 (NCT04424316) is a Phase 3 study that assessed the efficacy of ABRYSVO in the prevention of RSV-associated lower respiratory tract disease (LRTD) in infants born to individuals vaccinated during pregnancy. The study evaluated the efficacy of ABRYSVO to prevent RSV-associated LRTD and severe RSV-LRTD in infants within 90, 120, 150, and 180 days after birth. Participants were randomized (1:1) to receive ABRYSVO (0.5 mL dose) or placebo (0.5 mL dose containing the same buffer ingredients in the same quantities as in a single dose of ABRYSVO [see Description (11)]). This study includes sites in both the northern and southern hemispheres. Vaccine efficacy (VE) was defined as the relative risk reduction of the endpoints of severe LRTD caused by RSV and LRTD cause by RSV in infants born to individuals who received ABRYSVO compared to infants born to individuals who received placebo. The demographic characteristics of Study 1 are described in Clinical Trials Experience Section 6.1.

Maternal participants were randomized (1:1) to receive ABRYSVO (3,695) or placebo (3,697). RSV-associated LRTD in infants was defined as a medically attended visit with a reverse transcription-polymerase chain reaction (RT-PCR) confirmed RSV illness with one or more of the following respiratory symptoms: tachypnea (respiratory rate ≥60 breaths/minute [<2 months of age], ≥50 breaths/minute [≥2 to 12 months of age], or ≥40 breaths/minute [≥12-24 months of age]); SpO2 measured in room air <95%; chest wall indrawing. RSV-associated severe LRTD was a subset defined as meeting the LRTD RSV criteria plus at least one of the following: tachypnea (respiratory rate ≥70 breaths per minute [<2 months of age], ≥60 breaths per minute [≥2 to 12 months of age], or ≥50 bpm [≥12 to 24 months of age]); SpO2 measured in room air <93%; high-flow nasal cannula or mechanical ventilation (invasive or noninvasive), ICU admission for >4 hours and/or failure to respond/unconscious. Secondary efficacy endpoints included hospitalizations due to RSV.

The VE results met the statistical criterion for success (a CI lower bound >20%) for reducing severe LRTD due to RSV, at all timepoints to within 180 days. The VE results did not meet the statistical criterion for success (a CI lower bound >20%) for reducing LRTD due to RSV; however, clinically meaningful efficacy was observed after 90 days through 180 days after birth.

Vaccine efficacy information is presented in Tables 6 to 10.

14.2 Efficacy in Individuals 60 Years of Age and Older

Study 3 (NCT05035212) is an ongoing Phase 3, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of ABRYSVO in the prevention of RSV-associated lower respiratory tract disease in individuals 60 years of age and older. Participants are planned to be followed for up to two RSV seasons, approximately 25 months.

Participants were randomized (1:1) to receive ABRYSVO (n=17,197) or placebo (n=17,186). Randomization was stratified by age, 60-69 years (n=21,499, 63%), 70-79 years (n=10,948, 32%), and ≥80 years (n=1,934, 6%). Healthy adults and adults with stable chronic diseases were included. Among enrolled participants 15% had stable chronic cardiopulmonary conditions such as chronic obstructive pulmonary disease (COPD), asthma, or congestive heart failure (CHF).

Starting 14 days after study vaccination (study Day 15), all participants were actively monitored for onset of acute respiratory illness (ARI) symptoms: new or increased sore throat, nasal congestion, nasal discharge, cough, wheezing, sputum production, or shortness of breath. If the participant experienced 1 or more ARI symptoms, a mid-turbinate nasal swab was collected within 7 days of onset of symptoms and tested by reverse transcriptase polymerase chain reaction (RT-PCR) for RSV.

RSV-associated lower respiratory tract disease (RSV-LRTD) was evaluated in Study 3. A case of RSV-LRTD was defined as an RT-PCR confirmed RSV illness with two or more, or three or more, of the following respiratory symptoms within 7 days of symptom onset and lasting more than 1 day during the same illness: new or increased cough, wheezing, sputum production, shortness of breath, or tachypnea (≥25 breaths/min or 15% increase from resting baseline). A case of RSV-associated severe lower respiratory tract disease was defined as a case meeting the RSV-LRTD criteria plus at least one of the following: hospitalization due to RSV-LRTD, new or increased oxygen supplementation, or mechanical ventilation including Continuous Positive Airway Pressure (CPAP).

Efficacy against Respiratory Syncytial Virus-associated Lower Respiratory Tract Disease in Individuals 60 Years of Age and Older

Vaccine efficacy (VE), against RSV-LRTD, defined as the relative risk reduction of first episode of RSV-LRTD in the ABRYSVO group compared to the placebo group in the first RSV season, was assessed.

The study met the pre-specified success criteria for demonstration of efficacy of ABRYSVO for the primary objectives of prevention of RSV-LRTD with ≥2 symptoms and prevention of RSV-LRTD with ≥3 symptoms. The median duration of follow-up for efficacy was 7 months.

Vaccine efficacy information is presented in Table 11.

There were 2 cases of RSV-associated severe lower respiratory tract disease in the placebo group and no cases in the ABRYSVO group.

14.3 Concomitant Vaccine Administration with Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed

Study 4 (NCT04071158) was a Phase 2, placebo-controlled, randomized, observer-blind study to evaluate the safety, tolerability, and immunogenicity of ABRYSVO (at dose levels 120 µg and 240 µg, with or without Al(OH)3) when administered concomitantly with Tdap in non-pregnant women 18 through 49 years of age.

Antibody responses to antigens contained in ABRYSVO and Tdap were assessed 1 month after vaccination in a population of non-pregnant adult individuals. Lower geometric mean antibody concentrations (GMCs) to the acellular pertussis antigens (pertussis toxin [PT], filamentous hemagglutinin (FHA), and pertactin [PRN]) were observed when ABRYSVO was administered concomitantly with a tetanus, diphtheria and acellular pertussis vaccine (Tdap) compared to pertussis GMCs when Tdap was administered alone. The lower limit (LL) of the 2-sided 95% confidence interval of the GMC ratio (GMC ABRYSVO+Tdap /GMC Tdap) was 0.64 for PT, 0.50 for FHA, and 0.48 for PRN, which did not meet the pre-specified non-inferiority criterion (lower limit of the 95% confidence interval for the GMC ratio is >0.67). The clinical relevance of this finding is unknown. The non-inferiority criteria for tetanus, diphtheria and RSV vaccine antigens were met [see Drug Interactions (7)].

16.1 How Supplied

ABRYSVO vial and prefilled syringe presentation is supplied in cartons of 1, 5, and 10 kits, without needles. Each kit includes a vial of Lyophilized Antigen Component (NDC 0069-0207-01), a prefilled syringe containing Sterile Water Diluent Component (NDC 0069-0250-01), and a vial adapter.

ABRYSVO vial and vial presentation is supplied in cartons of 5 and 10 doses packaged without syringes or needles. Each carton includes vials of Lyophilized Antigen Component (NDC 0069-0207-01) and vials of Sterile Water Diluent Component (NDC 0069-0651-01).

The vial stopper and the tip cap and rubber plunger of the prefilled syringe are not made with natural rubber latex.

16.2 Storage and Handling

Storage Before Reconstitution

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Discard if the carton has been frozen.