GlaxoSmithKline

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

Active immunization for the prevention of LRTD caused by respiratory syncytial virus (RSV) in individuals 60 years of age and older

Active immunization for the prevention of LRTD caused by RSV in individuals 60 years of age and older

Active immunization for the prevention of LRTD caused by RSV in individuals 50 through 59 years of age who are at increased risk for LRTD caused by RSV

Single dose (0.5 mL) as an intramuscular injection

After reconstitution, administer immediately or store at room temperature (15°C to 30°C [59°F to 86°F]) and use within 4 hours; discard constituted vaccine if not used within 4 hours

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

Supplied as a pre-filled syringe that contains a frozen suspension that must be thawed prior to administration.

Carton of one pre-filled syringe in single blister pack:

If thawed in refrigerator, thaw between 2°C to 8°C (36°F to 46°F) for 60 minutes. Let each pre‑filled syringe stand at room temperature for between 10 and 20 minutes before administering the vaccine.

If thawed at room temperature, thaw between 15°C to 25°C (59°F to 77°F) for 45 minutes. If thawed at room temperature, the vaccine is ready to be administered.

Carton of 10 pre-filled syringes in blister packs:

If thawed in refrigerator, thaw between 2°C to 8°C (36°F to 46°F) for 155 minutes. Let each pre‑filled syringe stand at room temperature for between 10 and 20 minutes before administering the vaccine.

If thawed at room temperature, thaw between 15°C to 25°C (59°F to 77°F) for 140 minutes. If thawed at room temperature, the vaccine is ready to be administered. 

Pre-filled syringes may be stored at 8°C to 25°C (46°F to 77°F) for a total of 24 hours after removal from refrigerated conditions. Discard the thawed pre-filled syringe if not used within this time.

A placebo-controlled, phase 2 randomized, observer-blind study (NCT04071158) was conducted to evaluate the safety, tolerability, and immunogenicity of ABRYSVO (at dose levels 120 mcg and 240 mcg, 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 tetanus, diphtheria and acellular pertussis vaccine (Tdap) were assessed 1 month after vaccination in non-pregnant adult individuals. The lower limits of the 95% confidence intervals for the geometric mean antibody concentrations (GMCs) ratios were 0.64 for pertussis toxin, 0.50 for filamentous hemagglutinin, and 0.48 for pertactin, 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 noninferiority criteria for tetanus, diphtheria, and RSV vaccine antigens were met.

In an open-label, Phase 3, clinical study (NCT04841577) conducted in New Zealand, Panama, and South Africa, participants 60 years of age and older received 1 dose of Arexvy and Fluarix Quadrivalent at Month 0 (n= 442) or 1 dose of Fluarix Quadrivalent at Month 0 followed by a dose of Arexvy at Month 1 (n= 443).

There was no evidence for interference in the immune response to any of the antigens contained in both concomitantly administered vaccines.

Data is not available for concomitant administration with other vaccines.

Mechanism of action

Active immunization: Induces an immune response against RSV pre-F that protects against lower respiratory tract disease caused by RSV

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

Contraindications

Preventing and Managing Allergic Vaccine Reactions: Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration. ​

Syncope: Fainting may occur in association with administration of injectable vaccines, including Abrysvo, Arexvy, and mRESVIA. Procedures should be in place to avoid injury from fainting. ​

Altered Immunocompetence: Immunocompromised persons, including those receiving immunosuppressive therapy, may have a diminished immune response to Abrysvo, Arexvy, and mRESVIA.

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

Limitations of Vaccine Effectiveness: vaccination with Abrysvo may not protect all vaccine recipients.

Adverse events (≥10%)​ age ≥60 years

Injection site pain

Fatigue

Myalgia/muscle pain

Headache

Arthralgia

Axillary swelling or tenderness

Chills

10.5%

15.5%

10.1%

12.8%

--

--

--

60.9%

33.6%

28.9%

27.2%

18.1%

--

--

55.9%

30.8%

25.6%

26.7%

21.7%

15.2%

11.6%

Adverse events (≥10%)​ age 50-59 years

Injection site pain

Fatigue

Myalgia/muscle pain

Headache

Arthralgia

Erythema

Swelling

75.8%

39.8%

35.6%

31.7%

23.4%

13.2%

10.4%

Adverse events (≥10%)​ pregnant patients

Injection site pain

Myalgia/muscle pain

Headache

Nausea

40.6%

26.5%

31.0%

20.0%

Data from a clinical trial that pregnant individuals who received Abrysvo at 24 through 36 weeks' gestation revealed no evidence for vaccine-associated increase in the risk of congenital anomalies or fetal deaths. In this study, there was a numerical imbalance in preterm births, with more preterm infants born to individuals in the Abrysvo group compared to individuals in the placebo group.​

Abrysvo has not been studied in pregnant individuals less than 24 weeks gestational age, and those at increased risk for preterm birth.

In a clinical study that enrolled pregnant individuals who received an investigational unadjuvanted RSV vaccine that contained the same RSVPreF3 antigen as Arexvy, an increase in preterm births was observed compared to pregnant individuals who received placebo (sucrose reconstituted with saline).

Arevxy is not approved for use in persons <50 years of age.

There is no human data to establish whether there is a vaccine-associated risk with use of MRESVIA in pregnancy.

MRESVIA is not approved for use in persons <60 years of age.

It is not known if the vaccines are excreted in human milk; data are not available to assess the effects of vaccines on the breastfed infant or on milk production/excretion

Safety and effectiveness in infants born to individuals vaccinated at younger than 10 years of age and non-pregnant individuals younger than 18 years of age via active immunization have not been established

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

In Study 3 (NCT05035212), of the 17,215 recipients who received Abrysvo, 62% (n= 10,756) were aged 60-69 years of age, 32% (n= 5,488) were 70-79 years of age, and 6% (n= 970) were ≥80 years of age

Of the total number of participants (N= 24,966) who received Arexvy or placebo in Study 1 (NCT04886596), 13,943 (55.8%) were 60 to 69 years of age, 8,978 (36%) were 70 to 79 years of age, and 2,045 (8.2%) were 80 years of age and older

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

Adjuvant suspension component vials and lyophilized antigen component vials: store refrigerated between 2°C and 8°C (36°F and 46°F); store in the original package in order to protect vials from light. Do not freeze. Discard if the adjuvant suspension component or antigen component have been frozen.

Store frozen between -40°C to ‑15°C (-40°F to 5°F).

Storage after thawing:

Pre-filled plastic syringes may be stored refrigerated between 2°C to 8°C (36°F to 46°F) for up to 30 days prior to use.

Pre-filled plastic syringes may be stored between 8°C to 25°C (46°F to 77°F) for a total of 24 hours after removal from refrigerated conditions; discard the pre-filled syringe if not used within this time. Syringes should not be returned to the refrigerator after being thawed at room temperature. Do not refreeze once thawed. Do not shake.

Abbreviations: LRTD= lower respiratory tract disease; preF= perfusion F protein; RSV= Respiratory Syncytial Virus; GMC= Geometric Mean Antibody Concentrations; Tdap= Tetanus, Diphtheria and Acellular Pertussis vaccine 

Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults

Design

Ongoing, international, randomized, placebo-controlled, phase 3 trial

N= 24,966

Objective

To show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season

Study Groups

AS01_E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA, Arexvy; n= 12,467)

Placebo (n= 12,499)

Inclusion Criteria

Adults 60 years of age or older who had not previously been enrolled in or were not currently enrolled in another RSV vaccine trial; individuals who were medically stable in the opinion of the investigator at the time of first vaccination

Exclusion Criteria

Any confirmed or suspected immunosuppressive or immunodeficient condition resulting from disease or immunosuppressive/cytotoxic therapy based on medical history and physical examination; history of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine; hypersensitivity to latex; serious or unstable chronic illness; history of dementia or any medical condition that moderately or severely impaired cognition; recurrent or uncontrolled neurological disorders or seizures; Planned or actual administration of a vaccine not foreseen by the study protocol in the period starting 30 days before each dose and ending 30 days after each dose of study vaccine administration, with the exception of inactivated and subunit influenza vaccines, which could be administered up to 14 days before or from 14 days after each study vaccination; previous vaccination with an RSV vaccine

Methods

Before the RSV season began, participants were randomly assigned in a 1:1 ratio to receive either the RSVPreF3 OA vaccine or placebo. Surveillance for acute respiratory infection was done by means of spontaneous reporting by participants and actively by means of scheduled contact with participants. During the assessment visit, nasal and throat swabs were obtained by trial personnel if the presence of acute respiratory infection was confirmed. Swabs were tested for RSV A and B subtypes by quantitative RT-PCR.

RSV seasons are from October 1 to April 30 in the northern hemisphere and from March 1 to September 30 in the southern hemisphere.

Duration

Enrollment: May 25, 2021, to January 31, 2022

Follow-up: median of 6.7 months, maximum of 10.1 months

Outcome Measures

Primary: vaccine efficacy against RT-PCR-confirmed RSV-related lower respiratory tract disease (LRTD) during one season

Secondary: vaccine efficacy against severe RSV-related lower respiratory tract disease, RSV-related acute respiratory infection, and RSV A and B subtypes

Baseline Characteristics

RSVPreF3 OA
(n= 12,467)

Placebo
(n= 12,499)

Age, years

≥ 80 yr

69.5±6.5

8.2%

69.6±6.4

8.2%

Female

Race

White

Black

79.3%

8.5%

79.5%

8.8%

Geographic region*

Northern Hemisphere

Southern Hemisphere

92.2% 

7.8%

92.2% 

7.8%

Type of residence

Community

Long-term care facility

98.7%

1.3%

98.8%

1.2%

Frailty status

Frail

Prefrail

Fit

Unknown

1.5%

38.4%

59.9%

0.2%

1.4%

38.3%

60.2%

0.2%

Charlson comorbidity index

3.2±1.2

3.2±1.2

Coexisting conditions of interest

Any preexisting condition

Cardiorespiratory preexisting condition

Endocrine or metabolic preexisting condition

39.6%

20.0%

25.7%

38.9%

19.4%

25.9%

* Northern Hemisphere countries that were included in the trial were Belgium, Canada, Estonia, Finland, Germany, Italy, Japan, Mexico, Poland, Russia, Spain, South Korea, the United Kingdom, and the United States. Southern Hemisphere countries were Australia, New Zealand, and South Africa.

Results

Endpoint

RSVPreF3 OA

No. of Participants/No. of Events

Follow-up

participant-yr

Incidence Rate

no. of events/1000 participant-yr

No. of Participants/No. of Events

Follow-up

participant-yr

Incidence Rate

no. of events/1000 participant-yr

Overall

Severe‡

12,466/ 7

12,466/ 1

6,865.9

6,867.9

1.0

0.1

12,494/ 40

12,494/ 17

6,857.3

6,867.7 

5.8

2.5 

82.6 (57.9 to 94.1)

94.1 (62.4 to 99.9) 

According to RSV subtype§

RSV A

RSV B

12,466/ 2

12,466/ 5

6,867.4

6,866.7

0.3

0.7

12,494/ 13

12,494/ 26

6,868.9

6,862.3

1.9

3.8

84.6 (32.1 to 98.3)

80.9 (49.4 to 94.3) 

RSV-related acute respiratory infection

Overall

According to RSV subtype§

RSV A

RSV B

12,466/ 9

12,466/ 18

6,865.2

6,861.7 

1.3

2.6

12,494/ 32

12,494/ 61

6,862.3

6,849.4

4.7

8.9

71.9 (39.7 to 88.2)

70.6 (49.6 to 83.7)

Solicited reactions

Any solicited reaction

Any grade 3 solicited reaction

Pain

Erythema

Swelling

Fever

Headache

Fatigue

Myalgia

Arthralgia

632

36

535

66

48

18

239

295

254

159

71.9 (68.8–74.9)

4.1 (2.9–5.6)

60.9 (57.5–64.1)

7.5 (5.9–9.5)

5.5 (4.1–7.2)

2.0 (1.2–3.2)

27.2 (24.3–30.3)

33.6 (30.4–36.8)

28.9 (25.9–32.0)

18.1 (15.6–20.8)

245

8

81

7

5

3

111

141

72

56

27.9 (25.0–31.0)

0.9 (0.4–1.8)

9.3 (7.4–11.4)

0.8 (0.3–1.6)

0.6 (0.2–1.3)

0.3 (0.1–1.0)

12.6 (10.5–15.0)

16.1 (13.7–18.7)

8.2 (6.5–10.2)

6.4 (4.9–8.2)

Serious adverse events

Any serious adverse event

Serious adverse events related to vaccine or placebo

Fatal serious adverse event

Fatal serious adverse event related to vaccine or placebo

522

10

49

3 

4.2 (3.8–4.6)

0.1 (0.0–0.1)

0.4 (0.3–0.5)

-- 

506

7

58

3 

4.0 (3.7–4.4)

0.1 (0.0–0.1)

0.5 (0.4–0.6)

-- 

Unsolicited adverse events

Any unsolicited adverse event

Grade 3 unsolicited adverse event

131

12

14.9 (12.6–17.4)

1.4 (0.7–2.4)

128

12

14.6 (12.3–17.1)

1.4 (0.7–2.4)

Potential immune-mediated disease

Any potential immune-mediated disease

Potential immune-mediated disease related to vaccine or placebo

40

7

0.3 (0.2–0.4)

0.1 (0.0–0.1) 

34

5

0.3 (0.2–0.4)

<0.1 (0.0–0.1) 

† Vaccine efficacy was estimated with the use of the Poisson method, with adjustment for age and geographic region, except for the analysis according to age, which was adjusted only for geographic region. A 96.95% confidence interval was used for the analysis of the primary end point (overall RSV-related lower respiratory tract disease), and a 95% confidence interval was used for all other end points. There was no adjustment for multiplicity, and the 95% confidence intervals should, therefore, not be used in place of hypothesis testing.

‡ Severe disease was determined based on either of two case definitions: on the basis of clinical signs or investigator assessment or on the basis of receipt of supportive therapy. All 18 severe cases met the first case definition. Two of the 18 cases were confirmed by the adjudication committee as also meeting the second case definition (group assignments blinded). In addition to these 2 cases, another 2 participants received supplemental oxygen but did not have cases confirmed by the adjudication committee as meeting the second case definition at the time of the efficacy database-lock point.

§ The RSV subtype was unknown in one case of RSV-related lower respiratory tract disease and in two cases of RSV-related acute respiratory infection. All cases with unknown subtype were in the placebo group.

Vaccine efficacy was also observed among participants with coexisting conditions (94.6%) and among those with prefrail status (92.9%). Among frail participants, efficacy results were inconclusive because only two cases of RSV-related lower respiratory tract disease occurred.

* Solicited reactions were those for which reports were solicited through 4 days after injection. Unsolicited adverse events were included up to 30 days after injection. Serious adverse events and events of potential immune-mediated disease were included up to 6 months after injection, and those that were considered by the investigator to be related to vaccine or placebo were included until the safety database-lock point. Fatal adverse events were included until the safety database-lock point. Grade 3 events of erythema and swelling were defined as erythema or swelling with a diameter of more than 100 mm, and grade 3 fever as a body temperature above 39.0°C. For all other adverse events, grade 3 indicated that normal everyday activities were prevented by the event. Relatedness to the administration of vaccine or placebo was determined by the investigator.

Adverse Events

See result

Study Author Conclusions

A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions.

InpharmD Researcher Critique

The trial has several limitations, including the relatively small number of participants aged 80 years or older and those who are frail. Additionally, the ability to detect rare side effects among patients was limited. The operational challenges were further compounded by conducting the trial during the second year of the Covid-19 pandemic. Furthermore, public health measures implemented to control Covid-19 led to a decrease in RSV transmission and changed the timing of the RSV season. As a result, most RSV-related acute respiratory infection cases occurred earlier in the season than anticipated.

Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults

Design

N= 34,284

Objective

To evaluate the efficacy and safety of the bivalent respiratory syncytial virus (RSV) prefusion F protein-based (RSVpreF) vaccine in the first RSV season after injection

Study Groups

RSVPreF vaccine (n= 17,215)​

Placebo (n= 17,069)

Inclusion Criteria

≥ 60 years of age at the time of first study intervention administration; healthy with stable preexisting disease 

Exclusion Criteria

Immunocompromised patients (apart from stable human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection); bleeding diathesis or condition associated with prolonged bleeding; history of severe adverse reaction associated with a vaccine and/or severe allergic reaction (i.e., anaphylaxis) to any component of the study interventions or any related vaccine

Methods

Eligible individuals were randomized (1:1) to receive one intramuscular injection of unadjuvanted RSVpreF vaccine at a dose of 120 mcg (containing 60 mcg each of RSV A and RSV B antigens) or placebo. To match the appearance of the RSVpreF vaccine, the placebo injection was lyophilized without the addition of active ingredients (i.e., RSV A and RSV B preF antigens, which are based on the currently predominant Ontario and Buenos Aires genotypes, respectively).

For efficacy measurements, RSV infection was confirmed by means of reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay (or by means of nucleic acid amplification test if RT-PCR testing was unavailable) within 7 days after the onset of signs or symptoms.

Duration

Interim analysis data-cutoff date: July 14, 2022

Mean follow-up: 7 months 

Outcome Measures

Primary: vaccine efficacy against seasonal RSV-associated lower respiratory tract illness with at least two or at least three signs or symptoms lasting more than one day (i.e., cough, wheezing, sputum production, shortness of breath, or tachypnea)

Relative risk of a first episode of RSV-associated lower respiratory tract illness in the RSVpreF vaccine group as compared with the placebo group in the first RSV season and starting on day 15 after injection

Secondary: vaccine efficacy against RSV-associated acute respiratory illness 

Safety: reactogenicity events, unsolicited adverse events 

Baseline Characteristics

RSVpreF vaccine (n= 17,215)

Placebo (n= 17,069)

Age, years

60–69 yr

70–79 yr

≥80 yr

68.3 ± 6.14

62.5%

31.9%

5.6%

68.3 ± 6.18

62.6%

31.8%

5.6%

Male

Race or ethnicity

White

Black 

Asian

Hispanic or Latinx

78.3%

12.8%

7.9%

37.1%

78.3%

12.9%

7.8%

36.7%

Country 

United States

Argentina

Japan

59.9%

21.3%

6.7%

59.7%

21.4%

6.8%

≥1 Prespecified high-risk condition

Current tobacco use

Diabetes 

Lung disease 

Heart disease 

51.5%

15.3%

18.7%

11.4%

12.9%

51.7%

15.1%

19.2%

12.0%

13.1%

≥1 Chronic cardiopulmonary condition

Asthma

Chronic obstructive pulmonary disease

Congestive heart failure

15.1%

9.0%

5.9%

1.7%

15.5%

8.8%

6.1%

1.8%

The demographic characteristics were broadly similar across the trial groups, and the trial participants were representative of the older population at risk for RSV-related illness. 

Results

Endpoint

RSVpreF vaccine (n= 17,215)

Placebo (n= 17,069)

Vaccine efficacy (96.66% confidence interval [CI])

RSV-associated lower respiratory tract illness with ≥2 signs or symptoms, cases

RSV-associated lower respiratory tract illness with ≥3 signs or symptoms, cases 

RSV-associated acute respiratory illness, cases 

62.1% (95% CI 37.1 to 77.9) 

Vaccine efficacy values that were calculated in sensitivity analyses and according to RSV A and RSV B subgroups were generally similar to those of the primary endpoints, although the latter had wide confidence intervals reflecting small subgroup sizes. Vaccine efficacy was maintained through the end of the first RSV season. 

Subgroup analyses of the primary endpoints according to participant age group (60 to 69 years, 70 to 79 years, or ≥80 years) and risk status (no prespecified high-risk conditions or ≥1 prespecified high-risk condition) indicated similar vaccine efficacy across subgroups, with wide confidence intervals reflecting small subgroup sizes. 

Concerning five individual signs and symptoms of lower respiratory tract illness, wheezing and shortness of breath were more common among participants with at least three signs or symptoms (93.8% and 68.8%, respectively) than among those with at least two signs or symptoms (37.8% and 28.9%, respectively).

Adverse Events

Common Adverse Events: RSVpreF vaccine vs. placebo local reactions (12% vs. 7%); systematic events (27% vs. 26%); adverse events through 1 month after injection (9% vs. 8.5%; 1.4% vs. 1% injection-related)

Serious Adverse Events: 2.3% vs. 2.3%, with 3 cases considered to be associated with trial intervention 

First event: delayed allergic reaction 7 hours after injection of RSVpreF vaccine, with recovery on the same day

Second event: combination of diplopia, paresthesia of palms and soles, and oculomotor and abducens nerve paralysis 8 days after injection of the vaccine who had a medical history of diabetes mellitus; this event was retrospectively diagnosed as being consistent with the Miller–Fisher syndrome (a subset of the Guillain–Barré syndrome characterized by ophthalmoplegia, ataxia, and areflexia). A spinal tap and nerve-conduction studies were not performed, and the participant recovered. 

Third event: myocardial infarction that developed 6 days after injection of vaccine; this participant then underwent angioplasty and later received a diagnosis of acute inflammatory demyelinating polyradiculoneuropathy, consistent with Guillain–Barré syndrome, that began 7 days after injection.

Percentage that Discontinued due to Adverse Events: None 

Study Author Conclusions

RSVpreF vaccine prevented RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness in adults (≥60 years of age), without evident safety concerns.

InpharmD Researcher Critique

Older and frail adults aged ≥80 years remain underrepresented in the current trial, limiting the generalizability of study results to such population. Given the interim analysis of the current report, the long-term efficacy and safety of RSVpreF vaccine requires further investigation. Additionally, the need for re-vaccination to maintain and boost immune responses remains unknown. 

Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants

Design

Phase 3, randomized, multicenter, double-blind, placebo-controlled trial (MATISSE)

N= 7,358 mothers; 7,128 infants

Objective

To evaluate the efficacy and safety of maternal respiratory syncytial virus prefusion F protein-based vaccine (RSVpreF) vaccination in preventing RSV-associated lower respiratory tract illness in infants

Study Groups

RSVpreF (n= 3,682 mothers; 3,570 infants)

Placebo (n= 3,676 mothers; 3,558 infants)

Inclusion Criteria

Healthy women, age ≤ 49 years, at 24 through 36 weeks' gestation on day of planned injection, with an uncomplicated, singleton pregnancy and no known increased risk of pregnancy complications

Exclusion Criteria

High-risk pregnancies (e.g., those with a current risk of preterm birth, multiple pregnancy, or a previous infant with a clinically significant congenital anomaly)

Methods

Patients were randomized 1:1 to receive a single intramuscular injection of 120 mcg of RSVpreF vaccine (60 mcg each of RSV A and RSV B antigens) or placebo. 

Duration

Trial: June 17, 2020 through October 2, 2022

Follow-up: 360 days

Outcome Measures

Primary

Efficacy: medically attended severe RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth

Safety: reactogenicity and adverse events in the maternal participants and adverse events and newly diagnosed chronic medical conditions in infants from the time of informed consent to 1 month after injection

Secondary

Efficacy: medically attended RSV-associated lower respiratory tract illness, RSV-associated hospitalization, and medically attended lower respiratory tract illness of any cause, all occurring within 360 days after birth

Safety: serious adverse events and newly diagnosed chronic medical conditions from birth through 12 months of age (birth through 24 months of age in infants enrolled during the first trial year)

Baseline Characteristics

RSVpreF

Placebo

Age at injection, years

30.8 ± 3.6

Race

White

Black

Asian

64.7%

19.6%

12.3%

64.4%

19.7%

12.6%

Infant participants

Male

Gestational age at birth

24 to < 28 weeks

28 to < 34 weeks

34 to < 37 weeks

37 to < 42 weeks

≥ 42 weeks

< 0.1%

0.6%

5.0%

93.7%

0.6%

< 0.1%

0.3%

4.4%

94.3%

0.8%

Apgar score, 5 min

< 4

4 to < 7

7 to 10

Median (range)

0.2%

0.8%

99.0%

9 (1-10)

0.1%

0.8%

99.1%

9 (2-10)

Outcome

Normal

Congenital malformation or anomaly

Other neonatal problems

89.9%

4.9%

6.1%

88.5%

5.7%

5.6%

Birth weight

Extremely low, ≤ 1,000 g

Very low, > 1,000 to 1,500 g

Low, > 1,500 to 2,500 g

< 0.1%

< 0.1%

5.0%

< 0.1%

0.2%

4.1%

Developmental delay

Results

Endpoint

RSVpreF

(n= 3,495)

Placebo

(n= 3,480)

Vaccine efficacy (99.5% or 97.58% CI)

Medically attended severe RSV-associated lower respiratory tract illness

90 days after birth

120 days after birth

150 days after birth

180 days after birth

6 (0.2%)

12 (0.3%)

16 (0.5%)

19 (0.5%) 

33 (0.9%)

46 (1.3%)

55 (1.6%)

62 (1.8%) 

81.8% (40.6 to 96.3)

73.9% (45.6 to 88.8)

70.9% (44.5 to 85.9)

69.4% (44.3 to 84.1)

Medically attended RSV-associated lower respiratory tract illness

90 days after birth

120 days after birth

150 days after birth

180 days after birth

24 (0.7%)

35 (1.0%)

47 (1.3%)

57 (1.6%)

56 (1.6%)

81 (2.3%)

99 (2.8%)

117 (3.4%) 

57.1% (14.7 to 79.8)

56.8% (31.2 to 73.5)

52.5% (28.7 to 68.9) 

51.3% (29.4 to 66.8)

RSV-associated hospitalization

90 days after birth

180 days after birth

10 (0.3%)

19 (0.5%)

31 (0.9%)

44 (1.3%)

67.7% (15.9 to 89.5)

56.8% (10.1 to 80.7)

Medically attended lower respiratory tract illness of any cause

90 days after birth

186 (5.3%)

200 (5.7%)

7.0% (-22.3 to 29.3)

Safety

Local reactions

Redness

Swelling

Injection-site pain

7%

6%

41%

<1%

<1%

10%

Systemic events

Fever

Fatigue

Headache

Nausea

Muscle pain

Joint pain

Vomiting

Diarrhea

3%

46%

31%

20%

27%

12%

8%

11%

3%

44%

28%

19%

17%

11%

7%

12%

Maternal adverse events

Any

Serious

Immediate

Severe

Life-threatening

Related to vaccine or placebo

Special interest

Leading to withdrawal

13.8%

4.2%

<0.1%

1.7%

0.5%

0.4%

2.7%

0

13.1%

3.7%

<0.1%

1.3%

0.3%

0.2%

2.5%

0 

Infant adverse events

Any

Serious

Severe

Life-threatening

Related to vaccine or placebo

Special interest

Congenital anomaly

Newly diagnosed chronic medical condition

Leading to withdrawal

37.1%

15.5%

4.5%

1.0%

<0.1%

8.4%

4.8%

0.2%

0

34.5%

15.2%

3.8%

1.0%

0

7.2%

5.9%

0.2%

0

CI: confidence interval

Adverse Events

Study Author Conclusions

RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified.

InpharmD Researcher Critique

As the trial is conducted in low-income countries, the present vaccine efficacy may not be readily applicable to developed countries. Additionally, the trial excludes those with high-risk pregnancies, limiting the generalizability of study findings to at-risk populations. 

 Efficacy and Safety of an mRNA-Based RSV PreF Vaccine in Older Adults

Design

Randomized, double-blind, placebo-controlled, phase 2-3 trial

N= 35,541

Objective

To assess the safety and efficacy of the mRNA-1345 (mRESVIA) vaccine in preventing a first episode of respiratory syncytial virus (RSV)-associated lower respiratory tract disease in adults 60 years of age or older

Study Groups

mRNA-1345 (n= 17,734)

Placebo (n= 17,679)

Inclusion Criteria

Exclusion Criteria

History of congenital or acquired immunodeficiency, immunosuppressive condition, or immune-mediated disease, chronic administration (defined as more than 14 continuous days) of immunosuppressants or other immune-modifying drugs within 6 months, administration of immunoglobulins and/or any blood products within the 3 months, known history of poorly controlled hypertension or hypotension

Methods

Participants were randomized (1:1) to receive one dose of either mRNA-1345 or placebo. Efficacy was measured by the prevention of RSV-associated lower respiratory tract disease with two and three signs or symptoms. Safety was also comprehensively assessed.

Duration

Outcome Measures

Primary: Prevention of RSV-associated lower respiratory tract disease with at least two signs or symptoms, and with at least three signs or symptoms

Secondary: Prevention of RSV-associated acute respiratory disease

Baseline Characteristics

mRNA-1345 (n= 17,734)

Placebo (n= 17,679)

Age, years

Female

Race

White

Black

Asian

Other

Unknown

63.4%

12.4%

8.7%

15.1%

0.4%

63.4%

12.2%

8.6%

15.1%

0.6%

Frailty status

Fit

Vulnerable

Frail

Missing data

76.2%

15.9%

5.6%

2.2%

75.5%

16.4%

5.8%

2.3%

No. of coexisting conditions of interest

0

≥ 1

70.5%

29.5%

71.0%

29.0%

Risk factors for lower respiratory tract disease

Present

Congestive heart failure

Chronic obstructive pulmonary disease

Both

Absent

6.9%

1.2%

5.4%

0.3%

93.1%

7.0%

1.1%

5.5%

0.3%

93.0%

Results

Endpoint

mRNA-1345 (n= 17,734)

Placebo (n= 17,679)

Vaccine efficacy* (confidence interval [CI]**)

RSV-associated lower respiratory tract disease with ≥2 signs or symptoms

Overall

RSV subtype A

RSV subtype B

60-69 year group

70-79 year group

≥ 80 yr

9

3

6

8

1

0

55

36

19

33

22

0

83.7 (66.0 to 92.2)

91.7 (73.0 to 97.4)

68.5 (21.1 to 87.4)

76.0 (48.0 to 88.9)

95.4 (65.9 to 99.4)

Not evaluated

RSV-associated lower respiratory tract disease with ≥3 signs or symptoms

Overall

RSV subtype A

RSV subtype B

60-69 year group

70-79 year group

≥ 80 yr

3

1

2

3

0

0

17

10

7

11

6

0

82.4 (34.8 to 95.3)

90.0 (22.0 to 98.7)

71.5 (−37.0 to 94.1)

72.9 (2.8 to 92.4)

100 (N/A to 100)

Not evaluated

RSV-Associated Acute Respiratory Disease

Incidence per 1000 person-year

4.1

13.1

68.4 (50.9 to 79.7)

* Vaccine efficacy was defined as 1 − the hazard ratio (mRNA-1345 vs. placebo)×100%

** The confidence interval for vaccine efficacy was based on a stratified Cox proportional hazards model. In overall analyses, the adjusted 95.88% confidence interval was for RSV-associated lower respiratory tract disease with at least two symptoms. The 96.36% confidence interval was for RSV-associated lower respiratory tract disease with at least three symptoms. In subgroup analyses, the 95% confidence interval was calculated. It adjusted for person-years, defined as time from randomization to the earliest of several events like RSV-associated disease, 12 months after injection, discontinuation, death, or data cutoff date.

Adverse Events

The vaccine group reported higher incidences of local (58.7% vs 16.2%) and systemic (47.7% to 32.9%) adverse reactions compared to the placebo group. Most reactions were mild to moderate. Serious adverse events occurred in 2.8% of participants in both groups.

Study Author Conclusions

A single dose of the mRNA-1345 vaccine resulted in no evident safety concerns and led to a lower incidence of RSV-associated lower respiratory tract disease and of RSV-associated acute respiratory disease than placebo among adults 60 years of age or older.

InpharmD Researcher Critique