Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults
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Design
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Ongoing, international, randomized, placebo-controlled, phase 3 trial
N= 24,966
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Objective
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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
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Study Groups
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AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA, Arexvy; n= 12,467)
Placebo (n= 12,499)
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Inclusion Criteria
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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
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Exclusion Criteria
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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
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Methods
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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.
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Duration
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Enrollment: May 25, 2021, to January 31, 2022
Follow-up: median of 6.7 months, maximum of 10.1 months
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Outcome Measures
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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
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Baseline Characteristics
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RSVPreF3 OA (n= 12,467)
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Placebo (n= 12,499)
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Age, years
≥ 80 yr
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69.5±6.5
8.2%
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69.6±6.4
8.2%
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Female
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52% |
51.4% |
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Race
White
Black
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79.3%
8.5%
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79.5%
8.8%
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Geographic region*
Northern Hemisphere
Southern Hemisphere
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92.2%
7.8%
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92.2%
7.8%
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Type of residence
Community
Long-term care facility
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98.7%
1.3%
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98.8%
1.2%
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Frailty status
Frail
Prefrail
Fit
Unknown
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1.5%
38.4%
59.9%
0.2%
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1.4%
38.3%
60.2%
0.2%
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Charlson comorbidity index
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3.2±1.2
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3.2±1.2
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Coexisting conditions of interest
Any preexisting condition
Cardiorespiratory preexisting condition
Endocrine or metabolic preexisting condition
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39.6%
20.0%
25.7%
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38.9%
19.4%
25.9%
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* 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.
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Results
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Endpoint
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RSVPreF3 OA
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Placebo |
Vaccine Efficacy % (95% CI)† |
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No. of Participants/No. of Events
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Follow-up
participant-yr
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Incidence Rate
no. of events/1000 participant-yr
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No. of Participants/No. of Events
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Follow-up
participant-yr
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Incidence Rate
no. of events/1000 participant-yr
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% |
RSV-related lower respiratory tract disease |
Overall
Severe‡
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12,466/ 7
12,466/ 1
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6,865.9
6,867.9
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1.0
0.1
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12,494/ 40
12,494/ 17
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6,857.3
6,867.7
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5.8
2.5
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82.6 (57.9 to 94.1)
94.1 (62.4 to 99.9)
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According to RSV subtype§
RSV A
RSV B
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12,466/ 2
12,466/ 5
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6,867.4
6,866.7
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0.3
0.7
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12,494/ 13
12,494/ 26
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6,868.9
6,862.3
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1.9
3.8
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84.6 (32.1 to 98.3)
80.9 (49.4 to 94.3)
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RSV-related acute respiratory infection
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Overall
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12,466/ 27 |
6,858.7 |
3.9 |
12,494/ 95 |
6,837.8 |
13.9 |
71.7 (56.2 to 82.3) |
According to RSV subtype§
RSV A
RSV B
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12,466/ 9
12,466/ 18
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6,865.2
6,861.7
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1.3
2.6
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12,494/ 32
12,494/ 61
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6,862.3
6,849.4
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4.7
8.9
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71.9 (39.7 to 88.2)
70.6 (49.6 to 83.7)
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Solicited and Unsolicited Adverse Events after Receipt of a Single Dose of the RSVPreF3 OA Vaccine or Placebo * |
Event |
RSVPreF3 OA Group |
Placebo Group |
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Participants no. |
Incidence (95% CI) |
Participants no. |
Incidence (95% CI) |
Solicited reactions
Any solicited reaction
Any grade 3 solicited reaction
Pain
Erythema
Swelling
Fever
Headache
Fatigue
Myalgia
Arthralgia
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632
36
535
66
48
18
239
295
254
159
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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)
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245
8
81
7
5
3
111
141
72
56
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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)
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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
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522
10
49
3
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4.2 (3.8–4.6)
0.1 (0.0–0.1)
0.4 (0.3–0.5)
--
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506
7
58
3
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4.0 (3.7–4.4)
0.1 (0.0–0.1)
0.5 (0.4–0.6)
--
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Unsolicited adverse events
Any unsolicited adverse event
Grade 3 unsolicited adverse event
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131
12
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14.9 (12.6–17.4)
1.4 (0.7–2.4)
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128
12
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14.6 (12.3–17.1)
1.4 (0.7–2.4)
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Potential immune-mediated disease
Any potential immune-mediated disease
Potential immune-mediated disease related to vaccine or placebo
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40
7
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0.3 (0.2–0.4)
0.1 (0.0–0.1)
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34
5
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0.3 (0.2–0.4)
<0.1 (0.0–0.1)
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† 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.
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Adverse Events
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See result
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Study Author Conclusions
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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.
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InpharmD Researcher Critique
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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.
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