ABRYSVO® Clinical Studies

(Respiratory Syncytial Virus Vaccine)

14 CLINICAL STUDIES

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 8 to 12.

Table 8     Vaccine Efficacy of ABRYSVO Against Severe LRTD Caused by RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals (Study 1)*
CI – confidence interval; N – number of participants; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
The prespecified success criterion was met for this endpoint evaluation
†
Evaluable efficacy population
‡
99.5% CI at 90 days; 97.58% CI at later intervals

Time Period

ABRYSVO

Number of Cases

N=3,495†

PLACEBO

Number of Cases

N=3,480†

VE (%)

(CI)‡

90 days

6

33

81.8 (40.6, 96.3)

120 days

12

46

73.9 (45.6, 88.8)

150 days

16

55

70.9 (44.5, 85.9)

180 days

19

62

69.4 (44.3, 84.1)

Table 9     Vaccine Efficacy of ABRYSVO Against LRTD Caused by RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals (Study 1)*
CI – confidence interval; N – number of participants; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
The prespecified success criterion (a CI lower bound >20%) was not met for this endpoint evaluation at 90 days
†
Evaluable efficacy population
‡
99.5% CI at 90 days; 97.58% CI at later intervals

Time Period

ABRYSVO

Number of Cases

N=3,495†

PLACEBO

Number of Cases

N=3,480†

VE (%)

(CI)‡

90 days

24

56

57.1 (14.7, 79.8)

120 days

35

81

56.8 (31.2, 73.5)

150 days

47

99

52.5 (28.7, 68.9)

180 days

57

117

51.3 (29.4, 66.8)

Table 10     Vaccine Efficacy of ABRYSVO Against Severe LRTD Caused by RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals at 32 Through 36 Weeks Gestational Age (Study 1)*
CI – confidence interval; N – number of participants; n – number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
This descriptive subgroup analysis was not controlled for multiple comparisons; results from 90 days and 180 days are presented.
†
Evaluable efficacy population
‡
95% CI

Time Period

ABRYSVO

Number of Cases

N=1572†

PLACEBO

Number of Cases

N=1539†

VE (%)

(CI)‡

90 days

1

11

91.1 (38.8, 99.8)

180 days

6

25

76.5 (41.3, 92.1)

Table 11     Vaccine Efficacy of ABRYSVO Against LRTD Caused by RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals at 32 Through 36 Weeks Gestational Age (Study 1)*
CI – confidence interval; N – number of participants; n – number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
This descriptive subgroup analysis was not controlled for multiple comparisons; results from 90 days and 180 days are presented.
†
Evaluable efficacy population
‡
95% CI

Time Period

ABRYSVO

Number of Cases

N=1572†

PLACEBO

Number of Cases

N=1539†

VE (%)

(CI)‡

90 days

14

21

34.7 (-34.6, 69.3)

180 days

24

55

57.3 (29.8, 74.7)

Table 12     Vaccine Efficacy of ABRYSVO Against Hospitalization Due to RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals (Study 1)*
CI – confidence interval; N – number of participants; n – number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
NCT04424316
†
Evaluable efficacy population
‡
99.17% CI

Time Period

ABRYSVO

Number of Cases

N=3,495†

PLACEBO

Number of Cases

N=3,480†

VE (%)

(CI)‡

90 days

10

31

67.7 (15.9, 89.5)

120 days

15

37

59.5 (8.3, 83.7)

150 days

17

39

56.4 (5.2, 81.5)

180 days

19

44

56.8 (10.1, 80.7)

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=18,488) or placebo (n=18,479). Randomization was stratified by age, 60-69 years (n=23,152, 63%), 70-79 years (n=11,782, 32%), and ≥80 years (n=2,031, 6%). Healthy adults and adults with stable chronic diseases were included. Among enrolled participants 16% 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).

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 primary analysis of efficacy was conducted when 44 first-episode RSV-LRTD cases with ≥2 symptoms had accrued in the first RSV season. 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 for the primary analysis is presented in Table 13.

Table 13     Vaccine Efficacy of ABRYSVO Against RSV-LRTD - Individuals 60 years of Age and Older – Primary Analysis (Study 3)*
CI – confidence interval; N – number of participants; n = number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy (VE based on case count ratio is calculated as 1-(P/[1-P]), where P is the number of RSVpreF cases divided by the total number of cases)
*
NCT05035212
†
Evaluable efficacy population
‡
RSV-associated LRTD symptoms included the following: new or increased cough, wheezing, sputum production, shortness of breath, or tachypnea (≥25 breaths/min or 15% increase from resting baseline).

Efficacy Endpoint

ABRYSVO

N=16,306†

n

Placebo

N=16,308†

n

VE (%)

(96.66% CI)

First episode of RSV-associated lower respiratory tract disease with ≥2 symptoms‡

11

33

66.7 (28.8, 85.8)

First episode of RSV-associated lower respiratory tract disease with ≥3 symptoms‡

2

14

85.7 (32.0, 98.7)

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

Descriptive vaccine efficacy analyses at the end of the first RSV season are presented in Table 14. The median duration of follow-up for efficacy was 7.1 months.

Table 14     Descriptive Vaccine Efficacy Analyses of ABRYSVO Against RSV-LRTD - Individuals 60 years of Age and Older, End of First RSV Season (Study 3)*
CI – confidence interval; N – number of participants; n = number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy (VE based on case count ratio is calculated as 1-(P/[1-P]), where P is the number of RSVpreF cases divided by the total number of cases)
*
NCT05035212
†
RSV-associated LRTD symptoms included the following: new or increased cough, wheezing, sputum production, shortness of breath, or tachypnea (≥25 breaths/min or 15% increase from resting baseline).
‡
Evaluable efficacy population.
§
Subgroup of evaluable efficacy population with ≥1 significant underlying condition i.e. heart disease (including congestive heart failure), lung disease (including chronic obstructive pulmonary disease), asthma, diabetes mellitus, liver disease, renal disease, and current tobacco use.

Efficacy Endpoint

Analysis Population

ABRYSVO

n/N

Placebo

n/N

VE (%)

(95% CI)

First episode of RSV-associated lower respiratory tract disease with ≥2 symptoms†

Overall‡

15/18,058

43/18,076

65.1 (35.9, 82.0)

With ≥1 significant underlying condition§

8/9,377

22/9,432

63.6 (15.2, 86.0)

First episode of RSV-associated lower respiratory tract disease with ≥3 symptoms†

Overall‡

2/18,058

18/18,076

88.9 (53.6, 98.7)

With ≥1 significant underlying condition§

2/9,377

11/9,432

81.8 (16.7, 98.0)

14.3 Immunogenicity in Individuals 18 Through 59 Years of Age Considered to be at Increased Risk of LRTD caused by RSV

Study 4 was a Phase 3, multicenter, randomized, double‑blind, placebo‑controlled study to assess the safety and immunogenicity of ABRYSVO in individuals 18 through 59 years of age considered to be at increased risk of LRTD caused by RSV due to chronic medical conditions. Study 4 enrolled individuals who had chronic pulmonary (including asthma), cardiovascular (excluding isolated hypertension), renal, hepatic, neurologic, hematologic or metabolic disorders (including diabetes mellitus and hyper/hypothyroidism) [see Adverse Reactions (6.1)]. Effectiveness was assessed by comparison of the RSV neutralizing geometric mean titers (GMTs) and seroresponse rates of the evaluable immunogenicity population in Study 4 who received ABRYSVO (n=437) to those of a subgroup of individuals from select sites in the United States and Japan in Study 3 (n=410) (Tables 15 and 16). Participants in the Study 3 subgroup were 60 years of age or older; 44% had chronic medical conditions.

Non-inferiority was demonstrated for the ratio of neutralizing GMTs for RSV A and RSV B (Study 4/Study 3 subgroup; lower bounds of the 2‑sided 95% CIs >0.667) (Table 15), and the percentage difference in neutralizing titer seroresponse rates for RSV A and RSV B (Study 4 minus Study 3; lower bounds of the 2‑sided 95% CIs >-10%) (Table 16).

Table 15     Comparison of Model Adjusted RSV Neutralizing GMTs at 1 Month After Vaccination with ABRYSVO, 18 Through 59 Years at Increased Risk of LRTD caused by RSV (Study 4)* versus 60 Years and Older (Study 3)†
CI – confidence interval; GMR – geometric mean ratio; GMT – geometric mean titer
*
NCT05842967
†
NCT05035212
‡
Analysis of covariance adjusted with baseline titer and sex.
§
Non-inferiority was met if the lower bound of the 2-sided CI of adjusted GMR (Study 4/Study3) >0.667 (1.5-fold NI criterion) for both RSV A and RSV B.

RSV subgroups

Study 4*

18-59 years of age at high risk

N=435-437

Adjusted GMT‡

(95% CI)

Study 3†

≥60 years

N=408

Adjusted GMT‡

(95% CI)

Adjusted GMR‡,§

(95% CI)

A

41097 (37986, 44463)

26225 (24143, 28486)

1.57 (1.396, 1.759)

B

37416 (34278, 40842)

24680 (22504, 27065)

1.52 (1.333, 1.725)

Table 16     Comparison of RSV Neutralizing Titer Seroresponse* Rates 1 Month After Vaccination with ABRYSVO, 18 Through 59 Years at Increased Risk of LRTD caused by RSV (Study 4)† versus 60 Years and Older (Study 3)‡
CI - confidence interval
*
Seroresponse is defined as achieving a ≥4-fold rise from baseline if the baseline measurement is above the lower limit of quantitation (LLOQ). If the baseline measurement is below the LLOQ, a post-vaccination assay result ≥4 × LLOQ is considered a seroresponse.
†
NCT05842967
‡
NCT05035212
§
Non-inferiority was met if the lower bound of the 2-sided CI for the percentage difference (Study 4 minus Study 3) >-10% (10% NI criterion) for both RSV A and RSV B.

RSV subgroups

Study 4

18-59 years of age at high risk

N=435-437

% (95% CI)

Study 3

≥60 years

N=408

% (95% CI)

Percentage Difference§ (95% CI)

A

93 (90.3, 95.3)

88 (84.4, 91.0)

5.1 (1.2, 9.2)

B

93 (90.6, 95.5)

85 (81.2, 88.4)

8.3 (4.2, 12.6)

14.4 Concomitant Administration of ABRYSVO with a Seasonal Inactivated Influenza Vaccine

In Study 5 (NCT05301322) [see Adverse Reactions (6.1)], antibody responses to antigens contained in ABRYSVO and FLUAD QUADRIVALENT were assessed 1 month after vaccination in individuals 65 years of age and older.

Immunologic non-inferiority was demonstrated for concomitant administration of ABRYSVO and FLUAD QUADRIVALENT as compared to sequential administration. The lower limits of the 2-sided 95% CIs for the Geometric Mean Titer Ratio (GMR) (concomitant administration group versus sequential administration group) for RSV A and RSV B neutralizing titers (NT) and hemagglutination inhibition (HAI) titers against influenza strains A/Victoria, A/Darwin, B/Austria, and B/Phuket were above 0.667 (the predefined 1.5-fold non-inferiority criterion).

14.5 Concomitant Administration of ABRYSVO with Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed

Study 6 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)].

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Clinical Studies

14 CLINICAL STUDIES

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 8 to 12.

Table 8     Vaccine Efficacy of ABRYSVO Against Severe LRTD Caused by RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals (Study 1)*
CI – confidence interval; N – number of participants; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
The prespecified success criterion was met for this endpoint evaluation
†
Evaluable efficacy population
‡
99.5% CI at 90 days; 97.58% CI at later intervals

Time Period

ABRYSVO

Number of Cases

N=3,495†

PLACEBO

Number of Cases

N=3,480†

VE (%)

(CI)‡

90 days

6

33

81.8 (40.6, 96.3)

120 days

12

46

73.9 (45.6, 88.8)

150 days

16

55

70.9 (44.5, 85.9)

180 days

19

62

69.4 (44.3, 84.1)

Table 9     Vaccine Efficacy of ABRYSVO Against LRTD Caused by RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals (Study 1)*
CI – confidence interval; N – number of participants; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
The prespecified success criterion (a CI lower bound >20%) was not met for this endpoint evaluation at 90 days
†
Evaluable efficacy population
‡
99.5% CI at 90 days; 97.58% CI at later intervals

Time Period

ABRYSVO

Number of Cases

N=3,495†

PLACEBO

Number of Cases

N=3,480†

VE (%)

(CI)‡

90 days

24

56

57.1 (14.7, 79.8)

120 days

35

81

56.8 (31.2, 73.5)

150 days

47

99

52.5 (28.7, 68.9)

180 days

57

117

51.3 (29.4, 66.8)

Table 10     Vaccine Efficacy of ABRYSVO Against Severe LRTD Caused by RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals at 32 Through 36 Weeks Gestational Age (Study 1)*
CI – confidence interval; N – number of participants; n – number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
This descriptive subgroup analysis was not controlled for multiple comparisons; results from 90 days and 180 days are presented.
†
Evaluable efficacy population
‡
95% CI

Time Period

ABRYSVO

Number of Cases

N=1572†

PLACEBO

Number of Cases

N=1539†

VE (%)

(CI)‡

90 days

1

11

91.1 (38.8, 99.8)

180 days

6

25

76.5 (41.3, 92.1)

Table 11     Vaccine Efficacy of ABRYSVO Against LRTD Caused by RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals at 32 Through 36 Weeks Gestational Age (Study 1)*
CI – confidence interval; N – number of participants; n – number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
This descriptive subgroup analysis was not controlled for multiple comparisons; results from 90 days and 180 days are presented.
†
Evaluable efficacy population
‡
95% CI

Time Period

ABRYSVO

Number of Cases

N=1572†

PLACEBO

Number of Cases

N=1539†

VE (%)

(CI)‡

90 days

14

21

34.7 (-34.6, 69.3)

180 days

24

55

57.3 (29.8, 74.7)

Table 12     Vaccine Efficacy of ABRYSVO Against Hospitalization Due to RSV – Infants From Birth Through 6 Months of Age by Active Immunization of Pregnant Individuals (Study 1)*
CI – confidence interval; N – number of participants; n – number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy
*
NCT04424316
†
Evaluable efficacy population
‡
99.17% CI

Time Period

ABRYSVO

Number of Cases

N=3,495†

PLACEBO

Number of Cases

N=3,480†

VE (%)

(CI)‡

90 days

10

31

67.7 (15.9, 89.5)

120 days

15

37

59.5 (8.3, 83.7)

150 days

17

39

56.4 (5.2, 81.5)

180 days

19

44

56.8 (10.1, 80.7)

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=18,488) or placebo (n=18,479). Randomization was stratified by age, 60-69 years (n=23,152, 63%), 70-79 years (n=11,782, 32%), and ≥80 years (n=2,031, 6%). Healthy adults and adults with stable chronic diseases were included. Among enrolled participants 16% 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).

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 primary analysis of efficacy was conducted when 44 first-episode RSV-LRTD cases with ≥2 symptoms had accrued in the first RSV season. 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 for the primary analysis is presented in Table 13.

Table 13     Vaccine Efficacy of ABRYSVO Against RSV-LRTD - Individuals 60 years of Age and Older – Primary Analysis (Study 3)*
CI – confidence interval; N – number of participants; n = number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy (VE based on case count ratio is calculated as 1-(P/[1-P]), where P is the number of RSVpreF cases divided by the total number of cases)
*
NCT05035212
†
Evaluable efficacy population
‡
RSV-associated LRTD symptoms included the following: new or increased cough, wheezing, sputum production, shortness of breath, or tachypnea (≥25 breaths/min or 15% increase from resting baseline).

Efficacy Endpoint

ABRYSVO

N=16,306†

n

Placebo

N=16,308†

n

VE (%)

(96.66% CI)

First episode of RSV-associated lower respiratory tract disease with ≥2 symptoms‡

11

33

66.7 (28.8, 85.8)

First episode of RSV-associated lower respiratory tract disease with ≥3 symptoms‡

2

14

85.7 (32.0, 98.7)

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

Descriptive vaccine efficacy analyses at the end of the first RSV season are presented in Table 14. The median duration of follow-up for efficacy was 7.1 months.

Table 14     Descriptive Vaccine Efficacy Analyses of ABRYSVO Against RSV-LRTD - Individuals 60 years of Age and Older, End of First RSV Season (Study 3)*
CI – confidence interval; N – number of participants; n = number of cases; RSV – respiratory syncytial virus; VE – vaccine efficacy (VE based on case count ratio is calculated as 1-(P/[1-P]), where P is the number of RSVpreF cases divided by the total number of cases)
*
NCT05035212
†
RSV-associated LRTD symptoms included the following: new or increased cough, wheezing, sputum production, shortness of breath, or tachypnea (≥25 breaths/min or 15% increase from resting baseline).
‡
Evaluable efficacy population.
§
Subgroup of evaluable efficacy population with ≥1 significant underlying condition i.e. heart disease (including congestive heart failure), lung disease (including chronic obstructive pulmonary disease), asthma, diabetes mellitus, liver disease, renal disease, and current tobacco use.

Efficacy Endpoint

Analysis Population

ABRYSVO

n/N

Placebo

n/N

VE (%)

(95% CI)

First episode of RSV-associated lower respiratory tract disease with ≥2 symptoms†

Overall‡

15/18,058

43/18,076

65.1 (35.9, 82.0)

With ≥1 significant underlying condition§

8/9,377

22/9,432

63.6 (15.2, 86.0)

First episode of RSV-associated lower respiratory tract disease with ≥3 symptoms†

Overall‡

2/18,058

18/18,076

88.9 (53.6, 98.7)

With ≥1 significant underlying condition§

2/9,377

11/9,432

81.8 (16.7, 98.0)

14.3 Immunogenicity in Individuals 18 Through 59 Years of Age Considered to be at Increased Risk of LRTD caused by RSV

Study 4 was a Phase 3, multicenter, randomized, double‑blind, placebo‑controlled study to assess the safety and immunogenicity of ABRYSVO in individuals 18 through 59 years of age considered to be at increased risk of LRTD caused by RSV due to chronic medical conditions. Study 4 enrolled individuals who had chronic pulmonary (including asthma), cardiovascular (excluding isolated hypertension), renal, hepatic, neurologic, hematologic or metabolic disorders (including diabetes mellitus and hyper/hypothyroidism) [see Adverse Reactions (6.1)]. Effectiveness was assessed by comparison of the RSV neutralizing geometric mean titers (GMTs) and seroresponse rates of the evaluable immunogenicity population in Study 4 who received ABRYSVO (n=437) to those of a subgroup of individuals from select sites in the United States and Japan in Study 3 (n=410) (Tables 15 and 16). Participants in the Study 3 subgroup were 60 years of age or older; 44% had chronic medical conditions.

Non-inferiority was demonstrated for the ratio of neutralizing GMTs for RSV A and RSV B (Study 4/Study 3 subgroup; lower bounds of the 2‑sided 95% CIs >0.667) (Table 15), and the percentage difference in neutralizing titer seroresponse rates for RSV A and RSV B (Study 4 minus Study 3; lower bounds of the 2‑sided 95% CIs >-10%) (Table 16).

Table 15     Comparison of Model Adjusted RSV Neutralizing GMTs at 1 Month After Vaccination with ABRYSVO, 18 Through 59 Years at Increased Risk of LRTD caused by RSV (Study 4)* versus 60 Years and Older (Study 3)†
CI – confidence interval; GMR – geometric mean ratio; GMT – geometric mean titer
*
NCT05842967
†
NCT05035212
‡
Analysis of covariance adjusted with baseline titer and sex.
§
Non-inferiority was met if the lower bound of the 2-sided CI of adjusted GMR (Study 4/Study3) >0.667 (1.5-fold NI criterion) for both RSV A and RSV B.

RSV subgroups

Study 4*

18-59 years of age at high risk

N=435-437

Adjusted GMT‡

(95% CI)

Study 3†

≥60 years

N=408

Adjusted GMT‡

(95% CI)

Adjusted GMR‡,§

(95% CI)

A

41097 (37986, 44463)

26225 (24143, 28486)

1.57 (1.396, 1.759)

B

37416 (34278, 40842)

24680 (22504, 27065)

1.52 (1.333, 1.725)

Table 16     Comparison of RSV Neutralizing Titer Seroresponse* Rates 1 Month After Vaccination with ABRYSVO, 18 Through 59 Years at Increased Risk of LRTD caused by RSV (Study 4)† versus 60 Years and Older (Study 3)‡
CI - confidence interval
*
Seroresponse is defined as achieving a ≥4-fold rise from baseline if the baseline measurement is above the lower limit of quantitation (LLOQ). If the baseline measurement is below the LLOQ, a post-vaccination assay result ≥4 × LLOQ is considered a seroresponse.
†
NCT05842967
‡
NCT05035212
§
Non-inferiority was met if the lower bound of the 2-sided CI for the percentage difference (Study 4 minus Study 3) >-10% (10% NI criterion) for both RSV A and RSV B.

RSV subgroups

Study 4

18-59 years of age at high risk

N=435-437

% (95% CI)

Study 3

≥60 years

N=408

% (95% CI)

Percentage Difference§ (95% CI)

A

93 (90.3, 95.3)

88 (84.4, 91.0)

5.1 (1.2, 9.2)

B

93 (90.6, 95.5)

85 (81.2, 88.4)

8.3 (4.2, 12.6)

14.4 Concomitant Administration of ABRYSVO with a Seasonal Inactivated Influenza Vaccine

In Study 5 (NCT05301322) [see Adverse Reactions (6.1)], antibody responses to antigens contained in ABRYSVO and FLUAD QUADRIVALENT were assessed 1 month after vaccination in individuals 65 years of age and older.

Immunologic non-inferiority was demonstrated for concomitant administration of ABRYSVO and FLUAD QUADRIVALENT as compared to sequential administration. The lower limits of the 2-sided 95% CIs for the Geometric Mean Titer Ratio (GMR) (concomitant administration group versus sequential administration group) for RSV A and RSV B neutralizing titers (NT) and hemagglutination inhibition (HAI) titers against influenza strains A/Victoria, A/Darwin, B/Austria, and B/Phuket were above 0.667 (the predefined 1.5-fold non-inferiority criterion).

14.5 Concomitant Administration of ABRYSVO with Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed

Study 6 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)].
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