Summary Basis of Decision for Abrysvo

Clinical Pharmacology

Abrysvo is a bivalent vaccine containing two recombinant stabilized respiratory syncytial virus (RSV) prefusion F antigens from the two major antigenic subgroups, RSV-A and RSV-B. The fusion (F) glycoprotein is the main surface virus antigen which facilitates entry into the host cell and is highly conserved across RSV‑A and RSV‑B subgroups. Following intramuscular administration, the prefusion F antigens elicit an immune response, which protects against RSV-associated lower respiratory tract disease.

In infants born to mothers vaccinated with Abrysvo during pregnancy, protection against RSV-associated lower respiratory tract disease is due to transplacental transfer of RSV neutralizing antibodies. Adults 60 years of age or older are protected by active immunization.

Immunogenicity was assessed as part of the clinical efficacy evaluation of Abrysvo. Pharmacokinetic studies were not conducted, as they are not required for vaccine products according to relevant guidelines.

For further details, please refer to the Abrysvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Abrysvo in preventing lower respiratory tract disease (LRTD) caused by infection with respiratory syncytial virus (RSV) was supported by the results from two clinical efficacy, immunogenicity, and safety studies, C3671008 and C3671013.

Study C3671008: Infants from birth through 6 months of age by active immunization of pregnant individuals

The efficacy of maternal immunization with Abrysvo in the prevention of medically attended RSV‑associated LRTD in infants from birth through 6 months of age was evaluated based on the results from a randomized, double-blind, placebo-controlled Phase III study, C3671008. This study enrolled healthy pregnant women, aged 49 years or younger, who were at 24 to 36 weeks of gestation, with uncomplicated, singleton pregnancy and no known increased risk of pregnancy complications. In total, 7,392 maternal participants were randomized in a 1:1 ratio and received a single dose (0.5 mL) of Abrysvo (number of participants [n] = 3,695) or placebo (n = 3,697). The dose of RSV prefusion F antigen in Abrysvo was 120 mcg (60 mcg of RSV subgroup A antigen and 60 mcg of RSV subgroup B antigen, unadjuvanted).

Maternal participants with known increased risk of pregnancy complications were excluded from the study (body mass index greater than 40 kg/m² prior to pregnancy, pregnancies resulting from in vitro fertilization, pre‑eclampsia, eclampsia, or uncontrolled gestational hypertension, placental abnormalities, polyhydramnios or oligohydramnios, significant bleeding or blood clotting disorder, unstable endocrine disorders, including untreated hyperthyroidism, untreated hypothyroidism or untreated disorders of glucose intolerance).

Demographic characteristics were generally similar between the pregnant participants who received Abrysvo and those who received a placebo. Of the participants who received Abrysvo, 65% were White, 20% were Black or African American, and 29% were Hispanic/Latino. The median age of participants was 29 years (age range: 16 to 45 years). The median gestational age at vaccination was 31 weeks and 2 days. The median gestational age of infants at birth was 39 weeks and 1 day (gestational age range: 27 weeks and 3 days to 43 weeks and 6 days). Among the infants born to maternal participants, 51% were male and 49% were female.

Respiratory syncytial virus-associated LRTD 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: fast breathing, low oxygen saturation (oxygen saturation as measured by pulse oximetry [SpO₂] of less than 95%), and chest wall indrawing. Respiratory syncytial virus-associated severe LRTD was defined as an illness that met the criteria for RSV-associated LRTD and at least one of the following: fast breathing, low oxygen saturation (SpO₂ less than 93%), use of high‑flow nasal cannula or mechanical ventilation, admission to an intensive care unit for longer than 4 hours and/or failure to respond/unconscious.

The study objective was the assessment of vaccine efficacy, defined as the relative risk reduction of the endpoint in the Abrysvo group compared to the placebo group, for infants born to immunized mothers who received one dose of Abrysvo during pregnancy. There were two primary efficacy endpoints, assessed in parallel, severe RSV‑positive medically attended LRTD and RSV‑positive medically attended LRTD, occurring within 90, 120, 150, and 180 days after birth. Secondary efficacy endpoints included hospitalizations due to RSV.

The results obtained from study C3671008 demonstrated that Abrysvo was efficacious in the prevention of RSV-associated LRTD in infants, from birth through 6 months of age, who were born to maternal participants who received one dose of Abrysvo. Vaccine efficacy results met the statistical criterion for success (a confidence interval [CI] lower bound greater than 20%) for the co-primary endpoint of reducing severe LRTD due to RSV in infants at all timepoints (90 days through 180 days after birth). The vaccine efficacy against severe LRTD due to RSV was 81.8% (99.5% CI: 40.6%, 96.3%) within 90 days after birth and 69.4% (97.58% CI: 44.3%, 84.1%) within 180 days after birth. However, the vaccine efficacy results did not meet the statistical criterion for success (a CI lower bound greater than 20%) for the co-primary endpoint of reducing LRTD due to RSV in infants within 90 days after birth (at this time point the vaccine efficacy was 57.1% [99.5% CI: 14.7%, 79.8%]. At 120, 150 and 180 days after birth, the point estimates of vaccine efficacy remained over 50% and the lower bounds of the 97.58% CI were greater than 20%.

Given the study exclusion criteria, efficacy data are not available regarding the use of Abrysvo in immunocompromised pregnant women and women with high-risk pregnancies. Similarly, no data are available on subsequent immunization (boosting) with Abrysvo of the same maternal participants in future singleton pregnancies.

Efficacy in twin or other multiple pregnancy scenarios are also not included in the data submitted. Data on high-risk pregnant individuals (e.g., past maternal history of prematurity, gestational diabetes, pre-eclampsia, etc.) are also not available.

Study C3671013: Adults 60 years of age or older

The clinical efficacy of Abrysvo in preventing RSV-associated LRTD in older adults (60 years of age or older) is supported by the results from an ongoing Phase III, multicentre, randomized, double-blind, placebo-controlled study C3671013.

The study enrolled 32,614 participants who were randomized in a 1:1 ratio and received a single dose (0.5 mL) of Abrysvo (n = 16,306) or placebo (n = 16,308). Enrollment was stratified by age, 60 to 69 years (62%), 70 to 79 years (32%), and 80 years of age or older (6%). Healthy adults and adults with stable chronic diseases were included in the study. Of the enrolled participants, 15% had stable chronic cardiopulmonary conditions, such as chronic obstructive pulmonary disease, asthma, or congestive heart failure.

Demographic characteristics were generally similar between participants who received Abrysvo and those who received placebo. Of the participants who received Abrysvo, 51% were male, 78% were White, 13% were Black or African American and 37% were Hispanic/Latino. The median age of participants was 67 years (age range: 59 to 95 years).

The participants received an injection on Day 1. Starting on Day 15 until the end of the RSV season, participants were monitored for onset of acute respiratory illness symptoms. If the participant experienced one or more acute respiratory illness symptoms, the participant self-collected a nasal swab and an unplanned respiratory illness visit was scheduled within 7 days of symptom onset. During the illness visit, nasal swabs were collected from the participant and sent to a central lab for confirmation of RSV infection using a RT-PCR test.

Respiratory syncytial virus-associated LRTD was defined as RT-PCR-confirmed RSV illness with two or more, or three or more, of the following five respiratory symptoms: new or increased cough, wheezing, sputum production, shortness of breath or tachypnea (25 or more breaths/min at rest or a 15% increase in breathing rate from resting baseline). The observed symptoms needed to last more than one day and the RSV infection needed to be confirmed by RT-PCR within 7 days of symptom onset.

Respiratory syncytial virus-associated severe LRTD was defined as meeting the RSV-LRTD criteria above and at least one of the following: hospitalization due to RSV- associated LRTD, new or increased oxygen supplementation, or mechanical ventilation including continuous positive airway pressure.

The study objective was the assessment of vaccine efficacy, defined as the relative risk reduction of a first episode of RSV-associated LRTD in the Abrysvo group compared to the placebo group and starting 14 days after. The statistical success criterion for vaccine efficacy was determined as a confidence interval (CI) lower bound greater than 20% for RSV-LRTD with at least two symptoms and with at least three symptoms.

As of the data cut-off date of July 8, 2022, the interim analysis results demonstrated that the C3671013 study met the pre-specified success criterion for efficacy. Vaccine efficacy in preventing RSV-associated LRTD with at least two symptoms and with at least three symptoms were 66.7% (96.66% CI: 28.8%, 85.8%) and 85.7% (96.66% CI: 32.0%, 98.7%), respectively. The median duration of follow-up for efficacy was 7 months.

The vaccine efficacy data for the prevention of severe RSV-positive LRTD in adults 60 years of age and older are not currently included in the results. At the time of the interim analysis, the minimum number of first-episode severe RSV-LRTD cases had not accrued.

Immunogenicity

Infants born to vaccinated mothers

Vaccine immunogenicity in 111 pregnant women was evaluated in the Phase IIb study, C3671003. The vaccine elicited neutralizing antibodies against RSV-A and RSV-B antigens one month after vaccination.

The neutralizing antibodies were observed in infants born to vaccinated mothers. Based on the descriptive analysis, in these infants at birth (n = 100), the antibody geometric mean titres (GMTs) were 12.6- fold higher than those in infants born to mothers who received placebo. At 6 months after birth, the infants’ GMTs were 6.8- fold higher than those infants born to mothers who received placebo.

No correlation of immunogenicity with efficacy has been currently established for the vaccine.

Adults 60 Years of Age or Older

Abrysvo elicited neutralizing antibodies against RSV-A and RSV-B antigens one month after vaccination. The geometric mean fold rise for anti-RSV-A and anti-RSV-B antibodies remained 4- to 5-fold higher at 12 months after vaccination compared to prior vaccination. Additionally, testing Abrysvo with and without adjuvant did not notably enhance immune responses.

Conclusion on the clinical efficacy and uncertainties

Based on the currently available efficacy and immunogenicity evidence, the benefit-risk profile of Abrysvo administered as a single dose in pregnant women, aged 49 years or younger, who are between 32 and 36 weeks gestation, and in adults aged 60 years or older is favourable. The recommended dose of Abrysvo is 120 mcg of RSV stabilized prefusion F protein (60 mcg of RSV subgroup A antigen and 60 mcg of RSV subgroup B antigen, unadjuvanted) given as a single 0.5 mL dose. Data on the vaccine efficacy are currently limited to approximately 6 months after vaccination. No information is currently available on the long‑term protection.

Data are not available regarding the use of Abrysvo in immunocompromised individuals and individuals with high-risk pregnancies. Similarly, no data are available on subsequent immunization (boosting) with Abrysvo of the same maternal participants in future singleton pregnancies.

In addition, the data for individuals older than 80 years of age are limited.

Indication

The New Drug Submission for Abrysvo was filed by the sponsor with the following proposed indication:

• for the prevention of lower respiratory tract disease and severe lower respiratory tract disease caused by respiratory syncytial virus (RSV) in infants from birth through 6 months of age by active immunization of pregnant individuals.

• prevention of acute respiratory disease and lower respiratory tract disease (LRTD) caused by RSV in individuals 60 years of age and older by active immunization.

Health Canada revised the proposed indication to limit the target population of pregnant individuals to those at 32 through 36 weeks of gestation. In the data submitted for this New Drug Submission, an imbalance of preterm births was observed among infants whose mother received Abrysvo vaccination between 24 and 31 weeks of gestation. This was not observed among infants whose mothers received Abrysvo between 32 and 36 weeks gestation.

Therefore, to support safe use of the product, Health Canada approved the following indication:

Abrysvo (Respiratory Syncytial Virus Stabilized Prefusion F Subunit Vaccine) is a bivalent vaccine indicated for:

• active immunization of pregnant individuals from 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.

• the prevention of LRTD caused by RSV in individuals 60 years of age and older by active immunization.

For more information, refer to the Abrysvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Indication for pregnancy for infant protection

The safety profile of Abrysvo administered to pregnant individuals from 32 to 36 weeks of gestation for the prevention of RSV-associated LRTD in infants was evaluated based on data generated from the second interim safety analysis of the ongoing pivotal Phase III clinical study C3671008 (described in the Clinical Efficacy section). The study enrolled 7,392 healthy pregnant women, 49 years of age and younger, who received a single dose (0.5 mL) of Abrysvo or placebo. The dose of RSV prefusion F antigen in Abrysvo was 120 mcg (60 mcg of RSV subgroup A antigen and 60 mcg of RSV subgroup B antigen, unadjuvanted). The 7,126 infants born to the vaccinated study participants were exposed in utero to the maternal antibodies. Maternal participants were followed for 6 months after delivery. The infant participants were followed for the first year of the study and are planned to be followed for up to 24 months, while those in the second year of the study are planned to be followed for up to 12 months.

Solicited adverse reactions were monitored in all maternal participants within 7 days after vaccination. The most commonly reported reactions in the Abrysvo group compared to the placebo group included pain at site injection (40.6% vs 10.1%), fatigue (46.1% vs 43.8%), headache (31.0% vs 27.6%), and muscle pain (26.5% vs 17.1%). Unsolicited adverse events were monitored in all maternal participants within 28 days after administration of Abrysvo or placebo. The rates of unsolicited adverse events were similar in the Abrysvo and placebo groups (13.7% vs 13.1%), and there were no obvious safety signals. Serious adverse events occurred in 4.2% of the maternal participants in the Abrysvo group relative to 3.7% in the placebo group.

Unsolicited adverse events were monitored in the infant participants within 28 days after delivery and were reported in 37.1% of the infants born to maternal participants who received Abrysvo compared to 34.5% of the infants born to maternal participants who received placebo. All infant participants were monitored for serious adverse events (including congenital anomalies) and adverse events of special interest from birth through 24 months of age for those enrolled in the first year of study, and from birth through 12 months of age for those enrolled in the second year of study. The incidence of serious adverse events occurring any time during the study in infant participants was similar in the two groups (17.5% versus 17.5%). No severe or life‑threatening adverse events in infant participants were considered by investigators to be related to the maternal vaccination.

For adverse events of special interest, there was a noted numerical imbalance in preterm births among Abrysvo recipients compared with placebo recipients (5.7% versus 4.7%). No observed increase in mortality (one death in Abrysvo group, two deaths in the placebo group) was seen in the preterm births, but morbidity was not quantified. The imbalance of preterm births was observed among infants whose mothers received Abrysvo between 24 weeks and 31 weeks of gestation. This was not noted among infants whose mothers received Abrysvo between 32 weeks and 36 weeks of gestation. An imbalance was also observed in regard to low birth weights, but only in the youngest gestation age group of the maternal participants. Most of this imbalance came from investigational sites in South Africa and Argentina with no imbalance seen in the aggregate incidence among participants from high income countries such as Canada.

In a smaller supportive study (C3671003), 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. As a precaution, the indication for the use of Abrysvo in pregnant individuals is currently limited to those between 32 and 36 weeks of gestation.

All maternal and infant participants were monitored for deaths and withdrawals from the study following the administration of Abrysvo or placebo. There were no maternal deaths in the placebo group and one maternal death in the Abrysvo group due to postpartum hemorrhage that was determined to be unlikely associated with vaccination. Among the live born infants, there were 5 (0.1%) deaths in the Abrysvo group and 12 (0.3%) in the placebo group. None of these deaths was assessed as related to study intervention. No withdrawals were considered related to vaccine adverse events.

Safety and efficacy data for Abrysvo are currently limited to a single-dose administered to maternal participants for the first RSV season. The data submitted do not include assessing protection in subsequent RSV seasons for the same infants or passive protection of subsequent pregnancies. The data also do not include subsequent boosting of the same pregnant individuals for future singleton pregnancies.

Safety and efficacy in twin or other multiple pregnancy scenarios are also not included in the data submitted. Data on high-risk pregnant individuals (e.g., past maternal history of prematurity, gestational diabetes, pre-eclampsia, etc.) are not available.

Adults 60 years or older indication

The primary safety information from the study C6371013 (described in the Clinical Efficacy section), involving 17,215 participants, 60 years of age and older (3% of whom were enrolled in Canada), indicates a favourable safety profile of Abrysvo. The majority of participants completed the minimum 6-month follow-up. Common vaccine side-effects, such as fatigue, headache, pain at injection site, and muscle pain, reported within the initial 7 days after vaccination, were generally mild to moderate in severity. Despite 213 participants receiving multiple doses of Abrysvo at different trial sites, no discernible trend in safety events emerged. Serious adverse events potentially associated with treatment, including Guillain-Barre syndrome (one case), Miller Fisher syndrome (one case), and hypersensitivity reactions (one case), were reported. An observed imbalance in atrial fibrillation rates has prompted a post-authorization safety study to investigate this finding further. Importantly, the Abrysvo Product Monograph has been updated to appropriately identify these potential risks.

Conclusion on the clinical safety and uncertainties

Based on the available safety data, the overall safety profile of Abrysvo administered as a single dose in pregnant women, aged 49 years or younger, between 32 and 36 weeks of gestation, as well as in adults aged 60 years or older, is generally favourable. The data on the vaccine safety are currently limited to approximately 6 months post vaccination. The need for and time of revaccination remain to be determined. The data for individuals older than 80 years of age are limited. No data are currently available on the use of Abrysvo in high-risk populations (i.e., immunocompromised individuals and pregnant individuals with high-risk pregnancies).

Due to prior association with an increase in severe RSV disease, active immunization of infants and toddlers has not yet been attempted. The data in children younger than 16 years of age are currently lacking. While preterm infant outcomes were not associated with mortality in the main study, the morbidity was not quantified during follow-up.

Data on Abrysvo are also limited to a single dose given to pregnant women for the first RSV season and do not include assessing protection in subsequent RSV seasons for the same infants or passive protection of subsequent pregnancies. The data also do not include subsequent boosting of the same pregnant individuals for future singleton pregnancy. Data do not include safety use in twin or other multiple pregnancy scenarios. Data in high-risk pregnant individuals (e.g., past maternal history of prematurity, gestational diabetes, pre-eclampsia, etc.) are not available.

For more information, refer to the Abrysvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

The submitted non-clinical data support the use of Abrysvo for the specified indication.

Eight non-clinical immunogenicity (proof of concept) studies were performed to establish the primary pharmacodynamics of the vaccine. Non-clinical studies in cotton rats suggested increased neutralizing antibody responses against respiratory syncytial virus (RSV) subgroups A and B antigens contained in the vaccine formulation. In the cotton rat model, immunization with bivalent prefusion F protected animals challenged with infectious RSV and did not enhance respiratory pathology compared to a group that was previously immunized/exposed to live RSV.

The submitted non-clinical toxicology data included the repeat‑dose toxicity study (Study 17GR075) in rats and the developmental and reproductive toxicity study in rabbits (Study AB22373).

In the repeat-dose toxicity study, a vaccine formulation containing two times the antigen content of a single human dose of Abrysvo was administered by intramuscular injection to male and female Wistar Han rats, once every two or three weeks for a total of three doses. The vaccine formulation was tolerated without evidence of systemic toxicity and produced an expected local inflammatory reaction that was reversible. The study did not result in adverse anatomic pathology findings. It was also observed that the vaccine elicited a functional antibody response in rats.

The developmental and reproductive toxicity study assessed the potential effects of Abrysvo on fertility and embryo-fetal development in female New Zealand white rabbits and on the in utero and postnatal development of their offspring. The rabbits were administered four intramuscular doses of Abrysvo (two times the recommended human dose) twice before mating and twice during gestation. There was no indication of maternal systemic toxicity, nor any effects on mating performance or fertility in female rabbits or on embryo/fetal or postnatal survival, growth or development in the offspring. Abrysvo has not been evaluated for carcinogenicity and genotoxicity.

Overall, the vaccine was immunogenic in the relevant animal models. The animal challenge studies showed that the vaccine protected animals challenged with infectious RSV without evidence of vaccine‑associated enhanced disease. Non‑clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and toxicity to reproduction and development.

For more information, refer to the Abrysvo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Abrysvo is a bivalent prophylactic vaccine developed to prevent lower respiratory tract disease (LRTD) caused by infection with respiratory syncytial virus (RSV). The vaccine is intended to protect infants from birth through six months of age by immunizing pregnant individuals. In addition, a second indication is approved for Abrysvo for the prevention of lower respiratory tract disease in individuals 60 years of age or older.

The Abrysvo drug product is a sterile, preservative-free, lyophilized powder containing equal amounts of the RSV subgroup A and B fusion (F) glycoproteins stabilized in the prefusion conformation. Prior to administration by intramuscular injection, the drug product is reconstituted directly in the single-dose vial with sterile water diluent supplied in a pre-filled syringe. Each dose is intended to deliver 60 mcg each of RSV‑A and RSV‑B antigens, for a total of 120 mcg of protein per 0.5 mL dose. The supplied vaccine is unadjuvanted.

Characterization of the Drug Substance

Abrysvo contains versions of two proteins found on the surface of the virus called RSV subgroup A stabilized prefusion F and RSV subgroup B stabilized prefusion F.

Abrysvo works by ‘teaching’ the immune system (the body’s natural defences) how to defend the body against a disease. Abrysvo contains proteins from the surface of the RSV virus. When a person is given the vaccine, the immune system treats the viral proteins as ‘foreign’ and makes defences against them. If, later on, the vaccinated person comes into contact with the virus, the immune system will recognise the viral proteins and be prepared to attack it. This will help to protect against LRTD caused by the virus.

Comprehensive studies were performed to provide assurance that both antigens consistently exhibit the desired characteristic structure and biological activity. Several physicochemical tests were conducted to characterize the two antigens, including tests to evaluate intact mass, protein profile, primary, secondary and tertiary structure, charge distribution, non-glycosylated variants, and oxidation/deamidation levels.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The manufacturing process of Abrysvo involves cell culture and harvest, purification, and dispensing followed by freezing and storage. Each RSV subgroup A and B fusion glycoprotein (the drug substances) is manufactured separately.

Both recombinant RSV‑A and RSV‑B antigens are produced from genetically engineered Chinese hamster ovary (CHO) cell lines. The CHO cells are stably transfected with a deoxyribonucleic acid (DNA) plasmid bearing the sequence of the modified RSV F proteins. The transfected CHO cells are initially propagated in shake flasks and then transferred to bioreactors as the cell cultures grow. The cells are induced to express the antigens when the cell cultures have reached a targeted volume/density. Following sufficient cell expansion in the production bioreactor, the cells are harvested and cellular debris is removed. The clarified harvest undergoes a series of chromatography and filtration steps to purify and concentrate the antigen. Each drug substance is stored in a separate sterile container and is subsequently frozen.

The manufacturing process for the vaccine drug product begins with the thawing of the drug substances. Once thawed, both drug substances are filtered and then added to a formulation vessel. The drug substances are diluted with a formulation buffer to achieve the target drug product bulk concentration. Following formulation, the drug product bulk is filtered, aseptically filled into vials, and lyophilized. The vials are then stoppered, capped, and stored in a refrigerator between 2 °C and 8 °C. The diluent is sterile water for injection provided in syringes.

The manufacturing of Abrysvo involves the use of two facilities which meet the appropriate quality manufacturing standards. The manufacturing processes of the two drug substances and the final drug product include process parameters, in-process controls, critical quality attributes, analytical methods, and specifications which are based on manufacturing experience, internal assessments, and small-scale studies. The suitability of these small-scale studies was confirmed at the commercial scale. Analytical methods were validated or verified appropriately. The specifications for quality attributes were based on clinical trial materials and are supported by pharmacopoeial requirements, assay sensitivity, and process capability. The available batch analysis and stability data from the commercial scale drug substance and drug product lots demonstrate the ability of the manufacturing process to produce consistently high-quality drug substances and final drug product.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the RSV‑A and RSV‑B antigens with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The manufacturing processes include appropriate control strategies that adequately ensure the quality of the drug substance and drug product. All analytical procedures used for in-process, stability, and release testing of the drug substance and drug product were validated. The drug substance and drug product were tested against suitable reference standards to verify that they meet approved specifications.

Abrysvo is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the two drug substances (RSV‑A and RSV‑B) and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 24 months for Abrysvo is acceptable when stored between 2 °C and 8 °C in the original carton and protected from light.

Following reconstitution, Abrysvo should be administered immediately or stored between 15 °C and 30 °C and used within 4 hours after reconstitution. The reconstituted vaccine may not be stored under refrigerated conditions (2 °C to 8 °C) and may not be frozen.

Facilities and Equipment

Based on a risk assessment conducted by Health Canada, on-site evaluations (OSEs) of the drug substance and drug product manufacturing facilities were not deemed necessary. The OSE of the drug substance manufacturing site was waived due to several risk-mitigation factors. In addition, the risk assessment score for the drug product manufacturing site was determined to be below the values that indicate a need for OSE.

Adventitious Agents Safety Evaluation

None of the raw materials used in the production of Abrysvo are directly derived from animals. The drug substance antigens are produced in Chinese hamster ovary (CHO) cell cultures using chemically defined media that are free from any animal-derived components. Raw materials are purchased from approved suppliers, routinely tested, and must meet pre-defined specifications prior to use. A risk assessment for all raw materials was provided. The materials comply with the Note for Guidance on Minimizing the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products (EMEA/410/01, Revision 3) and the assessment confirmed that the risk of transmissible spongiform encephalopathy can be considered negligible. Viral clearance studies support the efficient clearance and inactivation of retrovirus like particles and viral contaminants during the purification steps of the drug substance manufacturing process. The measures in place are considered acceptable to ensure the absence of adventitious agents and to confirm the safety of the product.