Summary Basis of Decision for Abrysvo

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug
Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Abrysvo is located below.

Recent Activity for Abrysvo

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Abrysvo. When the PAAT for Abrysvo becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Abrysvo

Date SBD issued: 2024-05-10

The following information relates to the New Drug Submission for Abrysvo.

Respiratory syncytial virus subgroup A and subgroup B stabilized prefusion F proteins

Drug Identification Number (DIN): 02544040 – 60 mcg/0.5 mL respiratory syncytial virus (RSV) subgroup A stabilized prefusion F protein and 60 mcg/0.5 mL RSV subgroup B stabilized prefusion F protein, powder for solution, intramuscular administration

Pfizer Canada ULC

New Drug Submission Control Number: 272785

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): J07 Vaccines

Date Filed: 2023-02-27

Authorization Date: 2023-12-21

On December 21, 2023, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the vaccine Abrysvo.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Abrysvo is favourable for the 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. Abrysvo is also authorized for the prevention of LRTD caused by RSV in individuals 60 years of age and older by active immunization.

1 What was approved?

Abrysvo, an active immunizing agent, was authorized for the:

  • 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.

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

The safety and efficacy of Abrysvo in individuals younger than 18 years of age have not been established. Limited data are available in pregnant adolescents and their infants.

Clinical studies include participants 65 years of age or older, and their data contribute to the overall assessment of safety and efficacy of Abrysvo.

Abrysvo (60 mcg/0.5 mL RSV subgroup A and 60 mcg/0.5 mL RSV subgroup B stabilized prefusion F proteins) is presented as a lyophilized powder for solution, which is reconstituted with sterile water for injection. The diluent is provided in a prefilled syringe, along with a vial adapter. In addition to the RSV subgroup A and B fusion (F) glycoproteins, the powder also contains the following non-medicinal ingredients: mannitol, polysorbate 80, sodium chloride, sucrose, tromethamine, and trometamol hydrochloride.

The use of Abrysvo is contraindicated in individuals who are hypersensitive to the active ingredient or to any ingredients in the formulation, including any non-medicinal ingredients, or components of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Abrysvo Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Abrysvo approved?

Health Canada considers that the benefit-harm-uncertainty profile of Abrysvo is favourable for the:

  • 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.

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

Respiratory syncytial virus is a highly contagious human ribonucleic acid virus which causes respiratory tract infections in people of all ages. Two antigenically distinct subtypes exist, RSV‑A and RSV‑B. During outbreaks of RSV infections, both subtypes are usually present in the community, but their relative proportions may differ between epidemics. A systematic analysis conducted in 195 countries in 2018 found that the incidence of LRTD caused by RSV in adults 70 years of age or older was 6.3 cases for every 1,000 people. Another recent worldwide systematic review and meta-analysis in adults aged 65 years or older found an estimated RSV-associated acute LRTD incidence rate of 6.7 cases per 1,000 person-years. Several comorbidities have been shown to be risk factors for serious RSV-caused respiratory illness, notably chronic obstructive pulmonary disease, cardiovascular conditions, diabetes mellitus, immunocompromised conditions, and frailty.

Globally, RSV is the leading cause of bronchiolitis and viral pneumonia in infants (children from birth to one year of age) which can lead to fatal respiratory distress, especially in younger infants with underlying cardiopulmonary disease. Risk factors for severe RSV infection and diseases in infants include prematurity, household with young siblings, attending daycare, as well as low maternal neutralizing antibodies. By the age of two years, nearly all children have evidence of a past RSV infection with short‑lived immunity resulting in repeated infections throughout life. Once infected with RSV, the RSV infection may result in greater morbidity or mortality among infants and the elderly, in comparison to young adults. In general, among industrialized countries in temperate climate regions with cold seasons, RSV causes more hospitalization among infants, but less mortality compared with the elderly.

Abrysvo is a bivalent vaccine developed to prevent LRTD caused by infection with RSV. Abrysvo contains two recombinant stabilized RSV prefusion F antigens, each representing the two major virus subgroups, RSV-A and RSV-B. The prefusion F antigen is the primary target of neutralizing antibodies that block the RSV infection. Following intramuscular administration, the prefusion F antigens elicit an immune response, that protects against RSV-associated LRTD. The Abrysvo vaccine is intended to prevent LRTD in infants from birth through 6 months of age by immunizing pregnant women that are between 32 and 36 weeks of gestation. Abrysvo is also intended to prevent LRTD in individuals 60 years or older.

Indication for pregnancy for infant protection

The clinical efficacy of Abrysvo in the prevention of RSV-associated LRTD in infants born to healthy mothers vaccinated during pregnancy was based on the results from a randomized, double-blind, placebo-controlled Phase III study, C3671008. This study enrolled healthy pregnant women, 49 years of age and younger, who were between 24 and 36 weeks of gestation. There were 7,392 maternal participants randomized in a 1:1 ratio to receive 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 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 from study C3671008 showed that Abrysvo was efficacious for the prevention of RSV‑associated LRTD in infants, from birth through 6 months of age, who were born to maternal participants who had received one dose of Abrysvo. The vaccine efficacy results met the statistical criterion for success (a lower boundary of the confidence interval [CI] greater than 20%) for reducing severe medically attended LRTD due to RSV, at all time points through 180 days. Abrysvo reduced the risk of developing RSV‑associated severe medically attended LRTD by 69.4% in infants within 180 days after birth. In the immunized maternal participants, Abrysvo elicited neutralizing antibodies against RSV‑A and RSV‑B one month following vaccination.

Abrysvo is considered safe for use in pregnant women aged 49 years or younger, if given between 32 and 36 weeks of gestation to minimize the risk of a premature birth. The safety profile of Abrysvo is based on the assessment of post‑vaccination reactions among maternal participants in the first seven days, other adverse events in the first 28 days, and serious adverse events including deaths in the first six months after injection. The safety evaluation was also based on events among infants including any adverse events in the first 28 days after birth, and serious adverse events (including deaths) and adverse reactions of special interest (e.g., premature birth, low birth weight, congenital anomalies).

Solicited adverse reactions were more commonly reported in the maternal participants who received Abrysvo compared to the placebo group. The most commonly reported reactions among the maternal participants in the Abrysvo group relative to the placebo group were: pain at injection site (40.6% versus [vs] 10.1%), fatigue (46.1% vs 43.8%), headache (31.0% vs 27.6%), and muscle pain (26.5% vs 17.1%). The rates of other adverse events were balanced among the maternal participants in both groups (13.7% vs 13.1%) with no obvious safety signals. Serious adverse events within one month following vaccination were reported in 4.2% of the maternal participants in the Abrysvo group and 3.7% of the maternal participants in the placebo group. The rates of serious adverse events in the infant participants within one month following birth was 15.5% in those born to vaccinated mothers versus 15.2% in those born to mothers from the placebo group. No severe or life‑threatening adverse events in the infant participants were considered by investigators to be related to the maternal vaccination.

Given the study exclusion criteria, efficacy and safety 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.

Indication for adults 60 years of age or older

The clinical efficacy of Abrysvo for the active immunization of individuals 60 years of age or older is based on the results from an ongoing Phase III, multicentre, randomized, double‑blind, placebo‑controlled study C3671013. This study evaluated the efficacy and safety of Abrysvo in preventing RSV‑associated LRTD in older individuals during the first RSV season. The study enrolled 32,614 adults 60 years of age or older. Participants were randomized in a 1:1 ratio to receive a single dose of Abrysvo (number of participants [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%). 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 majority of the enrolled participants were healthy adults, whereas 15% had stable chronic cardiopulmonary conditions such as chronic obstructive pulmonary disease, asthma, or congestive heart failure.

Participants received an injection on Day 1. Starting on Day 15, 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 (on the second day and third day after onset of symptoms) 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.

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 study injection. 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 cutoff date of July 8, 2022, the interim analysis results demonstrated that the C3671013 study met the pre-specified success criterion for efficacy. Vaccine efficacy to prevent 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 severe RSV-positive lower respiratory tract illness are not currently included in the results. At the time the interim analysis was conducted, the minimum number of first-episode severe RSV-associated LRTD cases had not accrued.

The overall safety profile of Abrysvo is generally favourable. The majority of the participants in study C3671013 completed the minimum 6-month follow-up, and discontinuation rates were consistently distributed across groups. Common adverse events reported by the participants included: fatigue, headache, pain at injection site, and muscle pain. These adverse events were generally mild to moderate in severity and occurred within the initial 7 days after vaccination. 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 Abrysvo treatment include: Guillain-Barre syndrome (one case), Miller Fisher syndrome (one case), and hypersensitivity reactions (one case). An observed imbalance in atrial fibrillation rates was also noted which has prompted a post‑authorization safety study to investigate this finding further. Importantly, the product monograph has been updated to appropriately label these potential risks.

The data on the Abrysvo vaccine efficacy and safety for individuals 60 years of age or older are currently limited to approximately 6 months after vaccination. Currently, there is no information on the long-term protection and safety of Abrysvo.

The data for individuals older than 80 years of age are limited. The data in high-risk immunocompromised populations are not currently available.

A Risk Management Plan (RMP) for Abrysvo was submitted by Pfizer Canada ULC to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Abrysvo Product Monograph met the necessary regulatory labelling, plain language and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Abrysvo was accepted.

Overall, Abrysvo has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Abrysvo Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Abrysvo?

The Canadian regulatory decision on the Abrysvo New Drug Submission (NDS) was made independently based on the Canadian review. Communications between the sponsor and the United States Food and Drug Administration and the European Medicines Agency were used as supplemental references.

The review of the quality, non-clinical, and clinical components of the New Drug Submission (NDS) for Abrysvo was based on a critical assessment of the data package submitted to Health Canada. In addition, the reviews completed by the European Medicines Agency and the United States Food and Drug Administration were used as added references, as per Method 3 described in the Guidance Document: The Management of Drug Submissions and Applications. The Canadian regulatory decision regarding the Abrysvo NDS was made independently based on the Canadian review.

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Submission Milestones: Abrysvo

Submission Milestone

Date

Pre-submission meeting

2023-01-24

New Drug Submission filed

2023-02-27

Screening

Screening Acceptance Letter issued

2023-03-24

Review

Quality evaluation completed

2023-11-03

Review of Risk Management Plan completed

2023-12-12

Non-clinical evaluation completed

2023-12-18

Clinical/medical evaluation completed

2023-12-18

Biostatistics evaluation completed

2023-12-18

Labelling review completed

2023-12-18

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate

2023-12-21

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Food and Drug Regulations.

5 What post-authorization activity has taken place for Abrysvo?

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Abrysvo. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up-to-date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

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.

7.2 Non-Clinical Basis for Decision

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.

7.3 Quality Basis for Decision

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.