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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): GSK RSVPreF3 Vaccine (AREXVY)						Print
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			OverviewIntroductionMethodsResultsGRADE SummaryReferences
		
Overview
A Grading of Recommendations, Assessment, Development and Evaluation (GRADE) review of the evidence for benefits and harms for GSK Respiratory Syncytial Virus (RSV) PreF3 vaccine was presented to the Advisory Committee on Immunization Practices (ACIP) on June 21, 2023. GRADE evidence type indicates the certainty in estimates from the available body of evidence. Evidence certainty ranges from high certainty to very low certainty [*1*].
The policy questions were, “Should vaccination with GSK RSVPreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose administered intramuscularly [IM]), rather than no vaccine, be recommended in persons aged ≥65 years?” and “Should vaccination with GSK RSVPreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM), rather than no vaccine, be recommended in persons aged 60–64 years?” The benefits chosen by the ACIP RSV Vaccines Work Group (Work Group) as critical or important to policy decisions were prevention of RSV lower respiratory tract illness/disease (LRTI/LRTD) (critical), medically attended RSV LRTI/LRTD (critical), hospitalization for RSV respiratory illness (important), severe RSV respiratory illness requiring supplemental oxygen (O2) or other respiratory support (important), and death due to RSV respiratory illness (important). The harms chosen by the Work Group as critical or important to policy decisions were serious adverse events (critical), inflammatory neurologic events* (important) and reactogenicity grade ≥3 (important).
A systematic review of evidence on the efficacy and safety of GSK RSVPreF3 vaccine among persons aged 60 years and older was conducted. The quality of evidence from one Phase 3 randomized controlled trial (RCT) and one Phase 1/2 RCT were assessed using the GRADE approach [*2-4*]. Efficacy findings were based on analyses of data collected during May 2021–March 2023, which included two complete RSV seasons for Northern Hemisphere participants and one complete RSV season for Southern Hemisphere participants.
A lower risk of RSV LRTD† was observed with vaccination compared to placebo (incident rate ratio [IRR] 0.254, 95% confidence interval [CI]: 0.165, 0.379, evidence certainty: moderate), corresponding to a vaccine efficacy of 74.6% (95% CI: 62.1%, 83.5%)§. A lower risk of medically attended RSV LRTD¶was also observed (IRR 0.225; 95% CI: 0.110, 0.421; evidence certainty: moderate), corresponding to a vaccine efficacy of 77.5% (95% CI: 57.9%, 89.0%).** The trial was not powered to detect a lower risk of hospitalization for RSV respiratory illness or severe RSV respiratory illness requiring supplemental oxygen or other respiratory support (for both outcomes IRR 0.236; 95% CI: 0.005, 2.112; evidence certainty: very low), corresponding to a vaccine efficacy for both outcomes of 76.4% (95% CI: -111%, 99.5%). No deaths due to RSV respiratory illness were identified among vaccine recipients or placebo recipients.
In terms of harms, the pooled available data from the Phase 3 and Phase 1/2 RCTs indicated that serious adverse events (SAEs)†† were balanced between participants in the vaccine and placebo arms (risk ratio [RR] 1.019; 95% CI: 0.908, 1.145; evidence certainty: high). Reactogenicity grade ≥3§§ was associated with vaccination (RR 4.099; 95% CI: 1.989, 8.446; evidence certainty: high), with 3.8% of vaccine recipients and 0.9% of placebo recipients reporting any grade ≥3 local or systemic reactions following injection. No inflammatory neurologic events were observed within 42 days after injection in either placebo-controlled trial. However, inflammatory neurologic events were observed in other trials not included in the GRADE assessment due to lack of an unvaccinated comparator: one event of Guillain-Barré syndrome (GBS) reported within 42 days after vaccination in a recipient of the investigational vaccine in an open label trial without a placebo arm¶¶ and two events of acute disseminated encephalomyelitis (ADEM) reported within 42 days after coadministration of the investigational vaccine with standard dose seasonal influenza vaccine in a coadministration study (for one of these ADEM cases the investigator revised the diagnosis to hypoglycemia and dementia in June of 2023).¶¶Introduction
On May 3, 2023, the U.S. Food and Drug Administration (FDA) approved the Biologics License Application (BLA) for a single dose GSK RSV vaccine (AREXVY) for administration in adults 60 and older vaccine for prevention of RSV-associated lower respiratory tract disease [5]. GSK RSVPreF3 is a stabilized prefusion F subunit vaccine. As part of the process employed by the ACIP, a systematic review and GRADE evaluation of the evidence for GSK RSVPreF3 vaccine was conducted and presented to ACIP. The ACIP adopted a modified GRADE approach in 2010 as the framework for evaluating the scientific evidence that informs recommendations for vaccine use. Evidence of benefits and harms were reviewed based on the GRADE approach [1].  No conflicts of interest were reported by CDC and ACIP RSV Vaccines Work Group members involved in the GRADE analysis.
The policy questions were, “Should vaccination with GSK RSVPreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM), rather than no vaccine, be recommended in persons aged ≥65 years?” and “Should vaccination with GSK RSVPreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM), rather than no vaccine, be recommended in persons aged 60–64 years?” (Table 1).Methods
We conducted a systematic review of evidence on the efficacy and safety of GSK RSVPreF3 vaccine (120μg antigen + AS01E adjuvant). We assessed outcomes and evaluated the quality of evidence using the GRADE approach from August 2022 to June 2023.
Members were asked to pre-specify and rate the importance of relevant patient-important outcomes (including benefits and harms) before the GRADE assessment. Outcomes of interest included individual benefits and harms (Table 2). The critical benefits of interest selected by the Work Group were prevention of RSV lower respiratory tract illness/disease (LRTI/LRTD) and medically attended RSV LRTI/LRTD. Other important benefits of interest include hospitalization for RSV respiratory illness, severe RSV respiratory illness requiring supplemental oxygen or other respiratory support, and death due to RSV illness. Pre-specified harms of interest were serious adverse events (critical) and reactogenicity grade ≥3 (important). Inflammatory neurologic events were added as an additional important harm for consideration after the Work Group was made aware of inflammatory neurologic events in Season 1 safety data (important).
A systematic literature search was completed to review all available evidence on the efficacy and safety of GSK RSVPreF3 vaccine. Records of relevant observational studies as well as randomized control trials were included if they 1) provided data on persons aged ≥60 years vaccinated with RSVPreF3; 2) involved human subjects; 3) reported primary data; and 4) included data relevant to the efficacy and safety outcomes being measured. We identified relevant studies through Medline, Embase, Cochrane Library, CINAHL, Scopus, and clinicaltrials.gov. Relevant observational studies were restricted to the defined population, intervention, comparison, and outcome outlined in the policy question, or related outcomes if direct data were not available. In addition, unpublished relevant data were obtained by consulting with vaccine manufacturers. The systematic review was conducted as of January 31, 2023. Characteristics of all included studies are shown in Appendix 1 and evidence retrieval methods are found in Appendix 2.
The evidence certainty assessment addressed risk of bias, inconsistency, indirectness, imprecision, and other characteristics. The GRADE assessment across the body of evidence for each outcome was presented in an evidence profile; the evidence certainty of high, moderate, low, or very low certainty, respectively.
Incident rate ratios (IRR) were calculated using event counts and total person-time available from GSK’s pivotal phase 3 clinical trial. IRRs include follow-up time in two RSV seasons (May 2021 – April 2022 and August 2022 – March 2023) and are estimates of the ratio of the cumulative rates during this time. Vaccine efficacy estimates were defined as 100% x (1-IRR). In this clinical trial, some participants who received the RSV vaccine were re-randomized to receive a second dose 12 months after the first dose. Among those participants, efficacy follow up time after the second dose of RSV vaccine was excluded from this GRADE assessment; efficacy estimates in this assessment correspond only to a single dose of RSV vaccine, compared to placebo. Risk ratios used in the safety profile were calculated using counts of events and total participants available in the body of evidence, including both the phase 3 RCT and the phase 1/2 trial (estimates were pooled using R version 4.1.2).Results
The results of the GRADE assessment were presented to ACIP on Jun 21, 2023. Data were reviewed from one published, Phase 3 RCT and one published Phase 1/2 RCT, including additional unpublished data provided by the manufacturer and FDA [2-4, 6]. Characteristics of the included studies are shown in Appendix 1.
For evaluation of benefit outcomes, mean follow-up time was 15.3 months per participant.*** During this follow-up period, the GSK RSVPreF3 vaccine reduced the risk of RSV LRTD (vaccine efficacy: 74.6% [95% CI: 62.1%, 83.5%]) (Table 3a). GSK RSVPreF3 also reduced the risk of medically attended RSV LRTD (vaccine efficacy: 77.5% [95% CI: 57.9%, 89.0%]) (Table 3b). The trial was not powered to detect a lower risk of hospitalization for RSV respiratory illness nor severe RSV respiratory illness requiring supplemental oxygen or other respiratory support (vaccine efficacy for both outcomes was the same: 76.4% [95% CI: -111%, 99.5%] (Table 3c, Table 3d). No deaths due to RSV respiratory illness were identified among vaccine recipients or placebo recipients.
For evaluation of potential harms, proportions of participants with SAEs were comparable between the vaccine group and the placebo group (pooled RR: 1.019; 95% CI: 0.908, 1.145) (Table 3e, Table 4). One SAE (GBS) was considered by the study investigator and FDA to be related to vaccination; however, this SAE occurred outside of the trials included in the evidence profile and was not included in GRADE [6]. Grade ≥3, or severe, local or systemic reactions following vaccination, were reported by 3.8% of vaccine recipients and 0.9% of placebo recipients (pooled RR: 4.099; 95% CI: 1.989, 8.446) (Table 3f, Table 4). No inflammatory neurologic events were observed within 42 days after injection in trials included in GRADE. However, three inflammatory neurologic events were observed in trials excluded from the GRADE assessment due to lack of an unvaccinated comparator: one event of Guillain-Barré syndrome (GBS) reported within 42 days after vaccination with RSVPreF3 in an open label trial without a placebo arm and two events of acute disseminated encephalomyelitis (ADEM) reported within 42 days after coadministration of RSVPreF3 with standard dose seasonal influenza vaccine in a coadministration study.¶¶GRADE Summary
The initial GRADE evidence level was type 1 (high) for each outcome because the body of evidence consisted of randomized controlled trials (Table 4). In terms of critical benefits, the available data indicated that the vaccine was effective for preventing RSV LRTD and medically attended LRTD with moderate certainty. Certainty was downgraded once due to serious concern for indirectness (limited number of adults 80 and older included in the trial and the exclusion of persons with immune compromise).
The certainty in the effect estimate for hospitalization for RSV respiratory illness and severe RSV respiratory illness requiring supplemental oxygen or other respiratory support were both downgraded three times to very low certainty (once for serious concern for indirectness [again due to number of adults aged 80 years and older included in the trial and exclusion of persons with immune compromise] and twice for very serious concern for imprecision due to the 95% confidence interval for the measure of absolute risk including potential for both benefit and harm and fragility of the estimates)..No serious concerns impacted the certainty in the estimate for serious adverse events or reactogenicity (both high certainty). No inflammatory neurologic events were recorded in the phase 3 trial, meaning certainty of this outcome could not be assessed (however, 3 events were recorded outside of trials included in the GRADE evidence profile) (Table 4).Footnotes
*Inflammatory neurologic events were defined as Guillain-Barre Syndrome (including variants thereof), chronic inflammatory demyelinating polyneuropathy, and acute central nervous system inflammation (e.g., transverse myelitis, acute disseminated encephalomyelitis) occurring within 42 days after vaccination.
†RSV lower respiratory tract disease (LRTD) was defined by the presence of ≥2 lower respiratory symptoms or signs for ≥24 hours including ≥1 lower respiratory sign, or ≥3 lower respiratory symptoms ≥24 hours. Lower respiratory symptoms included new or increased sputum, new or increased cough, and new or increased dyspnea. Lower respiratory signs included new or increased wheezing, new or increased crackles or rhonchi based on chest auscultation, respiratory rate ≥20 respirations per minute, low or decreased oxygen saturation (<95% or ≤90% if baseline was <95%), and need for oxygen supplementation.
§Efficacy estimates were independently calculated by CDC using counts of events >14 days after injection and total person-time available from the GSK pivotal phase 3 trial (Efficacy=1 – incidence rate ratio x 100%). CDC method of efficacy estimation differed from manufacturer (manufacturer used a Poisson model with adjustment by covariates including season and participant age and region). When adjusting by participant age and region only, the manufacturer estimates efficacy of a single dose against RSV LRTD over two seasons to be 74.5% (97.5% CI: 60.0, 84.5). When also adjusting by season, the manufacturer estimates efficacy of a single dose against RSV LRTD over two seasons to be 67.2 % (97.5% CI: 48.2, 80.0).
¶ Medically attended LRTD was defined as attention at ≥1 inpatient or outpatient health care service. These estimates were not included in per-protocol assessments.
**Efficacy estimates were independently calculated by CDC using counts of events >14 days after injection and total person-time available from the GSK pivotal phase 3 trial (Efficacy=1 – incidence rate ratio x 100%). Estimates were based on analyses of data collected during May 2021–March 2023, which included two complete RSV seasons for Northern Hemisphere participants and one complete RSV season for Southern Hemisphere participants. Mean efficacy follow-up was approximately 15 months per participant. CDC method of efficacy estimation differed from manufacturer (manufacturer used a Poisson model with adjustment by covariates including season and participant age and region). When adjusting by participant age and region only, the manufacturer estimates efficacy of a single dose against RSV LRTD over two seasons to be 77.5% (95% CI: 57.9, 89.0). When also adjusting by season, the manufacturer estimates efficacy of a single dose against medically attended RSV LRTD over two seasons to be 73.1% (95% CI: 49.4, 86.9).
††Serious adverse events were defined as any untoward medical occurrence (during six months after injection in the phase 3 trial and 60 days after injection in the phase 1/2 trial) that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability or incapacity, or was a congenital anomaly or birth defect.
§§Severe reactogenicity events were defined as grade 3 solicited local reactions (injection site pain, redness and swelling) or systemic reactions (fatigue, fever, headache, gastrointestinal symptoms [nausea, vomiting, diarrhea or abdominal pain], arthralgia, myalgia and shivering) recorded during days 0–4 after vaccination in the phase 3 trial and days 0–7 after vaccination in the phase 1/2 trial. For injection site erythema and swelling, grade 3 corresponded to a diameter >100 mm. For fever, grade 3 corresponded to a temperature >39°C. For all other reactions, grade 3 corresponded to reactions that prevented normal, everyday activities. Grade 4 events were not defined in these trials.
¶¶ Across all RSVpreF clinical trials, inflammatory neurologic events were reported in three of 17,922 adults aged ≥60 years within 42 days after vaccination with RSVpreF3. One case was reported as GBS in a 78 year-old participant from Japan with symptom onset 9 days post-vaccination. It was recorded in a recipient of the investigational vaccine in an open label trial without a placebo arm. Two additional cases were reported in a trial of concomitant vaccination with the GSK RSVPreF3 vaccine and standard dose seasonal influenza vaccine. The first case was reported as ADEM in a 71-year-old male with symptom onset 7 days post-coadministration of the study vaccines. This case was fatal. The site investigator updated the diagnoses to hypoglycemia and dementia, rather than ADEM in June of 2023. The second case was reported as ADEM in a 71-year-old female with symptom onset 22 days post-coadministration of the study vaccines. In both cases the diagnosis of ADEM was based on symptoms and clinical findings only; diagnostic testing (including brain imaging, cerebrospinal fluid testing, and nerve conduction studies) was not performed, leading to uncertainty in the diagnoses. Available from: www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/06-RSV-Adults-Melgar-508.pdf.
*** Some study participants received a second dose of RSV vaccine. Inclusive of efficacy follow up time after a second dose of RSV vaccine, mean follow up time was 16.6 months per participant. Follow up time after a second dose of RSV vaccine was excluded from efficacy estimates in this GRADE assessment.References
Ahmed F. U.S. Advisory Committee on Immunization Practices (ACIP) Handbook for Developing Evidence-based Recommendations.
Papi A, Ison MG, Langley JM, et al. Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. NEJM. 2023; 388:595–608 https://doi.org/10.1056/NEJMoa2209604
Leroux-Roels I, David MG, Steenackers K, et al. Safety and Immunogenicity of a Respiratory Syncytial Virus Prefusion F (RSVPreF3) Candidate Vaccine in Older Adults: Phase 1/2 Randomized Clinical Trial, The Journal of Infectious Diseases, Volume 227, Issue 6, 15 March 2023, Pages 761–772, https://doi.org/10.1093/infdis/jiac327
GSK, 2023 personal communication, August 2022 – June 2023.
Food and Drug Administration (FDA). Approval letter: Arexvy. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2023 https://www.fda.gov/media/167806/download
Food and Drug Administration (FDA). FDA Briefing Document GSK RSV vaccine.  Vaccines and Related Biological Products Advisory Committee February 28 – March 1, 2023 Meeting Briefing Document- FDA: Applicant- GSKTop of PageTable 1: Policy Questions and PICO
Table 1: Policy Questions and PICO
Policy question:
Should vaccination with GSK RSVPreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM), rather than no vaccine, be recommended in persons aged ≥65 years?
Should vaccination with GSK RSVPreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM), rather than no vaccine, be recommended in persons aged 60–64 years?Population
Persons aged ≥60 yearsIntervention
GSK RSVPreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM)Comparison
No RSV vaccine (placebo)Outcomes
RSV lower respiratory tract illness/disease (LRTI/LRTD)
Medically attended RSV LRTI/LRTD
Hospitalization for RSV respiratory illness
Severe RSV respiratory illness requiring supplemental oxygen or other respiratory support
Death due to RSV respiratory illness
Serious Adverse Events (SAEs)
Inflammatory neurologic events (e.g., Guillain-Barré syndrome)
Reactogenicity (grade ≥3)**Abbreviations**: RSV= respiratory syncytial virus; IM = intramuscular; LRTD= lower respiratory tract disease; LRTI= lower respiratory tract illnessTable 2: Outcomes and Rankings
Table 2: Outcomes and Rankings
Outcome
Importance
Included in evidence profileRSV LRTI/LRTD)
Critical
YesMedically attended RSV LRTI/LRTD
Critical
YesHospitalization for RSV respiratory illness
Important
YesSevere RSV respiratory illness requiring O2/respiratory support
Important
YesDeath due to RSV respiratory illness
Important
NoaSerious adverse events
Critical
YesInflammatory neurologic events
Important
NoaReactogenicity (grade ≥3)
Important
Yes**Abbreviations**: RSV= respiratory syncytial virus; LRTD= lower respiratory tract disease; LRTI= lower respiratory tract illness; O2= Oxygen
aNo events occurred in the studies with these outcomes included in the review of evidence.Table 3a: Summary of Studies Reporting RSV Lower Respiratory Tract Disease (LRTD)a
Table 3a: Summary of Studies Reporting RSV Lower Respiratory Tract Disease (LRTD)
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb,c
n/N comparisonb
Comparator
Vaccine Efficacyd (95% CI)
Study limitations (Risk of Bias)Papi A, et al. 2023 plus unpublished data provided directly from the manufacturer[2,4]
LRTDa
30/12,469 (14662.6 person years observation)
139/12,498 (17269.0 person years observation)
Placebo
74.6% (62.1%, 83.5%)
Not serious
**Abbreviations:** CI = confidence interval
aLRTD defined as ≥2 lower respiratory symptoms or signs for ≥24 hours including ≥1 lower respiratory sign, or ≥3 lower respiratory symptoms ≥24 hours. Lower respiratory symptoms included new or increased sputum, new or increased cough, and new or increased dyspnea. Lower respiratory signs included new or increased wheezing, new or increased crackles or rhonchi based on chest auscultation, respiratory rate ≥20 respirations per minute, low or decreased oxygen saturation (<95% or ≤90% if baseline was <95%), and need for oxygen supplementation.
bBased on data collected from study initiation in May 2021 to data cutoff of March 31, 2023.
cIntervention was a single dose of GSK RSVpreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM).
d Efficacy estimates were independently calculated by CDC using counts of events >14 days after injection and total person-time available from the GSK pivotal phase 3 trial (Efficacy=1 – incidence rate ratio x 100%). Estimates were based on analyses of data collected during May 2021–March 2023, which included two complete RSV seasons for Northern Hemisphere participants and one complete RSV season for Southern Hemisphere participants. Mean efficacy follow-up was approximately 15 months per participant. CDC method of efficacy estimation differed from manufacturer (manufacturer used a Poisson model with adjustment by covariates including season and participant age and region). When adjusting by participant age and region only, the manufacturer estimates efficacy of a single dose against RSV LRTD over two seasons to be 74.5% (97.5% CI: 60.0, 84.5). When also adjusting by season, the manufacturer estimates efficacy of a single dose against RSV LRTD over two seasons to be 67.2 % (97.5% CI: 48.2, 80.0).Table 3b: Summary of Studies Reporting Medically Attended RSV LRTDa
Table 3b: Summary of Studies Reporting Medically Attended RSV LRTD
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb,c
n/N comparisonb
Comparator
Vaccine Efficacyd (95% CI)
Study limitations (Risk of Bias)Unpublished data provided directly from the manufacturer [4]
Medically attended RSV LRTDa
12/12,469 (14672.1 person years observation)
63/12,498 placebo arm (17307.8 person years observation)
Placebo
77.5% (57.9%, 89.0%)
Not serious
**Abbreviations:** RSV= respiratory syncytial virus; LRTD= Lower Respiratory Tract Disease;****CI = confidence interval.
aMedically attended LRTD was defined as LRTD plus attention at one or more inpatient or outpatient health care service. Estimates not included in per-protocol assessments.
bBased on data collected from study initiation in May 2021 to data cutoff of March 31, 2023.
cIntervention was a single dose of GSK RSVpreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM).
dEfficacy estimates were independently calculated by CDC using counts of events >14 days after injection and total person-time available from the GSK pivotal phase 3 trial (Efficacy=1 – incidence rate ratio x 100%). Estimates were based on analyses of data collected during May 2021–March 2023, which included two complete RSV seasons for Northern Hemisphere participants and one complete RSV season for Southern Hemisphere participants. Mean efficacy follow-up was approximately 15 months per participant. CDC method of efficacy estimation differed from manufacturer (manufacturer used a Poisson model with adjustment by covariates including season and participant age and region). When adjusting by participant age and region only, the manufacturer estimates efficacy of a single dose against medically attended RSV LRTD over two seasons to be 77.5% (95% CI: 57.9, 89.0). When also adjusting by season, the manufacturer estimates efficacy of a single dose against medically attended RSV LRTD over two seasons to be 73.1% (95% CI: 49.4, 86.9).Table 3c: Summary of Studies Reporting Hospitalization for RSV Respiratory Illnessa
Table 3c: Summary of Studies Reporting Hospitalization for RSV Respiratory Illness
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb,c
n/N comparisonb
Comparator
**Vaccine Efficacy**d**(95% CI) [100 x (1-IRR)]**
Study limitations (Risk of Bias)Unpublished data provided directly by the manufacturer [4]
Hospitalization for RSV respiratory illness
1/12469 (14676.5 person years observation)
5/12498 (17346.0 person years observation)
Placebo
76.4% (-111%, 99.5%)
Not Serious
**Abbreviations:** RSV= respiratory syncytial virus; CI = confidence interval.
a RSV-associated illness with an associated hospitalization.
bBased on data collected from study initiation in May 2021 to data cutoff of March 31, 2023.
cIntervention was a single dose of GSK RSVpreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM).
dEfficacy estimates were independently calculated by CDC using counts of events >14 days after injection and total person-time available from the GSK pivotal phase 3 trial (Efficacy=1 – incidence rate ratio x 100%). Estimates were based on analyses of data collected during May 2021–March 2023, which included two complete RSV seasons for Northern Hemisphere participants and one complete RSV season for Southern Hemisphere participants. Mean efficacy follow-up was approximately 15 months per participant. The manufacturer did not calculate efficacy for this outcome.Table 3d: Summary of Studies Reporting Severe RSV Respiratory Illness Requiring Oxygen/Respiratory Supporta
Table 3d: Summary of Studies Reporting Severe RSV Respiratory Illness Requiring Oxygen/Respiratory Support
Authors last name, pub year
Age or other characteristic of importance
n/N interventionb,c
n/N comparisonb
Comparator
**Vaccine Efficacyd (95% CI) [100 x (1-IRR)]**
Study limitations (Risk of Bias)Unpublished data provided directly by the manufacturer [4]
RSV respiratory illness requiring oxygen/respiratory support
1/12469 (14676.4 person years observation)
5/12498 (17345.9 person years observation)
Placebo
76.4% (-111%, 99.5%)
Not Serious
**Abbreviations:** CI = confidence interval; IRR = Incidence rate ratio.
aRSV-associated illness requiring oxygen supplementation, positive airway pressure, or other types of mechanical ventilation. If participant was already receiving any of these, significant change or adaptation was taken into account.
bBased on data collected from study initiation in May 2021 to data cutoff of March 31, 2023.
cIntervention was a single dose of GSK RSVpreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM).
dEfficacy estimates were independently calculated by CDC using counts of events >14 days after injection and total person-time available from the GSK pivotal phase 3 trial (Efficacy=1 – incidence rate ratio x 100%). Estimates were based on analyses of data collected during May 2021–March 2023, which included two complete RSV seasons for Northern Hemisphere participants and one complete RSV season for Southern Hemisphere participants. Mean efficacy follow-up was approximately 15 months per participant. The manufacturer did not calculate efficacy for this outcome.Table 3e: Summary of Studies Reporting Serious Adverse Eventsa
Table 3e: Summary of Studies Reporting Serious Adverse Events
Authors last name, pub year
Age or other characteristic of importance
n/N (%) interventionb
n/N (%) comparison
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Papi A, et al. 2023 plus additional unpublished data provided directly from the manufacturer [2,4]
Phase 3 RCT, persons aged ≥60 years
548/12,470 participantsc**,**d (4.4%)
539/12,503 participantsd (4.3%)
Placebo
1.02 (0.91, 1.15)
Not SeriousLeroux-Roels I, et. al. 2022 plus additional unpublished data provided directly from the manufacturer [3,4]
Phase 1/2 RCT, persons aged 60-80 years
1/100 participantse (1.0%)
1/101 participantse (1.0%)
Placebo
1.23 (0.054, 2.85)
Not Serious
**Abbreviations:**RR = relative risk; CI = confidence interval; RCT = randomized controlled trial.
a Serious adverse events were defined as any untoward medical occurrence (during six months after injection in the phase 3 trial and 60 days after injection in the phase 1/2 trial) that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability or incapacity, or was a congenital anomaly or birth defect.
bIntervention was a single dose of GSK RSVpreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM).
cOne SAE (GBS) was considered by the study investigator and FDA to be related to vaccination; however, this SAE occurred outside of the trials included in the evidence profile and was not included in GRADE.
dIncludes all events for 6 months after injection.
eIncludes all events after dose 1, but before dose 2 (day 61) in a placebo-controlled phase 1/2 dosing selection study.Table 3f: Summary of Studies Reporting Reactogenicitya
Table 3f: Summary of Studies Reporting Reactogenicity
Authors last name, pub year
Age or other characteristic of importance
n/N (%) interventionb
n/N (%) comparison
Comparator
RR (95% CI)
Study limitations (Risk of Bias)Papi A, et al. 2023 plus additional unpublished data provided directly from the manufacturer [2,4]
Phase 3 RCT, persons aged ≥60 years
36/879 participantsc
(4.1%)
8/878 participantsc (0.91%)
Placebo
4.49 (2.10, 9.61)
Not SeriousLeroux-Roels I, et. al. 2022 plus additional unpublished data provided directly from the manufacturer [3,4]
Phase 1/2 RCT, persons aged 60-80 years
1/100 participantsd (1.0%)
1/98 participantsd (1.0%)
Placebo
0.98 (0.06, 15.45)
Not Serious
**Abbreviations:**RR = relative risk; CI = confidence interval.
aSevere reactogenicity events were defined as grade 3 solicited local reactions (injection site pain, redness and swelling) or systemic reactions (fatigue, fever, headache, gastrointestinal symptoms [nausea, vomiting, diarrhea or abdominal pain], arthralgia, myalgia and shivering) recorded during days 0–4 after vaccination in the phase 3 trial and days 0–7 after vaccination in the phase 1/2 trial. For injection site erythema and swelling, grade 3 corresponded to a diameter >100 mm. For fever, grade 3 corresponded to a temperature >39°C. For all other reactions, grade 3 corresponded to reactions that prevented normal, everyday activities. Grade 4 events were not defined in these trials.
bIntervention was a single dose of GSK RSVpreF3 vaccine (120μg antigen + AS01E adjuvant, 1 dose IM).
cAll events within 7 days of injection.
dAll events within 4 days of injection.Table 4: Grade Summary of Findings Table
Table 4: Grade Summary of Findings Table
Certainty assessment
No of patients
Effect
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
GSK RSVpreF3 vaccine
no intervention
Relative
(95% CI)
Absolute
(95% CI)RSV lower respiratory tract disease (LRTD)1
randomised trials
not serious
not serious
seriousa,b
not serious
none
30/12469
139/12498
**Rate ratio 0.254**
(0.165 to 0.379)c
not estimabled
⨁⨁⨁◯
Moderate
CRITICALMedically attended RSV LRTD1
randomised trials
not serious
not serious
seriousa,b
not serious
none
12/12469
63/12498
**Rate ratio 0.225**
(0.110 to 0.421)c
**262 fewer per 100,000 patient(s) per RSV season**
(from 301 fewer to 196 fewer)f
⨁⨁⨁◯
Moderate
CRITICAL0.3%eHospitalization for RSV respiratory illness0
randomised trials
not serious
not serious
seriousa,b
very seriousg
none
1/12469
5/12498
**Rate ratio 0.236**
(0.005 to 2.112)c
**123 fewer per 100,000 patient(s) per RSV season**
(from 161 fewer to 180 more)i
⨁◯◯◯
Very low
IMPORTANT0.2%hSevere RSV respiratory illness requiring O2 supplementation or other respiratory support1
randomised trials
not serious
not serious
seriousa,b
very seriousg
none
1/12469
5/12499
**Rate ratio 0.236**
(0.005 to 2.112)c
**157 fewer per 100,000 patient(s) per RSV season**
(from 205 fewer to 229 more)k
⨁◯◯◯
Very low
IMPORTANT0.2%jDeath due to RSV respiratory illness1
randomised trials





0/12466 (0.0%)
0/12494 (0.0%)
not estimablel
not estimablel
–
IMPORTANTSerious adverse events (SAEs)2
randomised trials
not serious
not serious
not serious
not serious
none
549/12570 (4.4%)
540/12604 (4.3%)
**RR 1.019**
(0.908 to 1.145)m
**81 more per 100,000**
(from 394 fewer to 621 more)
⨁⨁⨁⨁
High
CRITICALInflammatory neurologic events within 42 days after injection2
randomised trials





0/12570 (0.0%)
0/12604 (0.0%)
not estimablen
not estimablen
–
IMPORTANTReactogenicity (injection site or systemic), grade ≥32
randomised trials
not serious
not serious
not serious
not serious
none
37/979 (3.8%)
9/976 (0.9%)
**RR 4.099**
(1.989 to 8.446)m
**2,858 more per 100,000**
(from 912 more to 6,866 more)
⨁⨁⨁⨁
High
IMPORTANT
**CI:** confidence interval; **RR:** risk ratio
Explanations
Concern for indirectness was noted due to the limited number of adults 80 and older included in the trial. Only 8% of the study population was aged ≥80 years; of the U.S. population aged ≥60 years, 16% is aged ≥80 years.
Concern for indirectness was noted due to exclusion of persons with immune compromise from the trial.
Rate ratio and the corresponding 95% CIs were calculated as 1- vaccine efficacy observed in the manufacturer’s phase 3 clinical trial for the specified outcome using all available follow-up time. This included follow-up time during May 2021–March 2023, which included two complete RSV seasons for Northern Hemisphere participants and one complete RSV season for Southern Hemisphere participants . The rate ratio is therefore an estimate of the ratio of the cumulative rates across both seasons, with a mean follow-up time per participant of 15.3 months. The input vaccine efficacy was calculated by CDC using reported case counts and person-time without adjustment for covariates. The CDC method of efficacy estimation differed from manufacturer method (Poisson model adjusted by season, participant age, and region). CDC estimates were higher than those produced by the manufacturer model.
An absolute effect could not be calculated for this outcome because there were no reliable data to estimate the true baseline rate of this outcome in the general population. The baseline rate captured in the placebo arm of the trial was felt to underestimate the true population-based incidence due to atypical RSV burden and seasonality during the COVID-19 pandemic. There were also no estimates of rate of ≥3 symptom RSV LRTI available in the literature.
This represents a control rate of 338 cases of medically attended RSV LRTI with ≥3 symptoms per 100,000 adults aged ≥60 years per RSV season (139 cases of medically attended RSV illness over one RSV season per 10,000 adults aged ≥60 years, of which 24.3% are RSV LRTI with ≥3 symptoms). Control rate data are from Belongia EA, et al. Clinical Features, Severity, and Incidence of RSV Illness During 12 Consecutive Seasons in a Community Cohort of Adults ≥60 Years Old. Open Forum Infect Dis. 2018 Nov 27;5(12):ofy316).
For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote e.
Very serious concern for imprecision was noted due to the small number of events observed in the trial. Certainty of evidence was downgraded twice, once because the 95% confidence interval for measure of absolute risk included potential for both benefit and harm and a second time because the rate ratio estimate was fragile (even one additional event in either arm would have significantly changed the estimate).
This represents a control rate of 162 cases of RSV-associated hospitalization over one RSV season per 100,000 adults aged ≥65 years. Control rate data are unpublished data from CDC’s RSV-NET, aggregated in a cost effectiveness analysis presented at the June 2023 ACIP meeting: www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-06-21-23/05-RSV-Adults-Ortega-Sanchez-508.pdf  .
For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote h.
This represents a control rate of 206 cases of severe RSV illness requiring supplemental oxygen or other respiratory support per 100,000 adults aged ≥60 years per RSV season (139 cases of medically attended RSV illness over one RSV season per 10,000 adults aged ≥60 years, of which 14.8% require supplemental oxygen in the 28 days after medical attention). Control rate data are from Belongia EA, et al. Clinical Features, Severity, and Incidence of RSV Illness During 12 Consecutive Seasons in a Community Cohort of Adults ≥60 Years Old. Open Forum Infect Dis. 2018 Nov 27;5(12):ofy316
For calculation of absolute effect, the baseline number of events was not taken from the placebo arm of the trial given concerns that the baseline captured in the trial underestimated the true population-based incidence. Instead the calculation uses the control rate described in footnote j.
Measures of relative and absolute effect could not be estimated due to zero events.
Pooled relative risk estimates were independently calculated using counts of events and participants in the pivotal phase 3 trial, as well as from the placebo-controlled phase 1/2 dosing selection study.
Measures of relative and absolute effect could not be estimated due to zero events in studies included in GRADE. In studies not included in GRADE there was one case of Guillain-Barré syndrome (GBS) reported within 42 days after vaccination in a recipient of RSVPreF3 in an open label trial without a placebo arm. There were also two cases of acute disseminated encephalomyelitis (ADEM) reported in a coadministration study of RSVPreF3 with standard dose seasonal influenza vaccine. Both ADEM cases were reported in the coadministration arm within 42 days after the intervention; no cases were reported in the sequential administration control arm. In both ADEM cases, the diagnosis was based on symptoms and clinical findings only; diagnostic testing (including brain imaging, cerebrospinal fluid testing, and nerve conduction studies) was not performed, leading to uncertainty in the diagnoses. For one of the ADEM cases, the investigator revised the diagnosis to hypoglycemia and dementia in June 2023. These studies were not included in GRADE assessment due to lack of an unvaccinated comparator.Appendix 1. Studies Included in the Review of Evidence
Appendix 1. Studies Included in the Review of Evidence
Last name first author, Publication year
Study design
Country (or more detail, if needed)
Participant age
Total population
N Intervention
N comparison
Outcomes
Funding sourcePapi A, et al. 2023 plus additional unpublished data provided directly from the manufacturer [2,4]
RCT Phase 3
Australia, Belgium, Canada, Estonia, Finland, Germany, Italy, Japan, Republic of Korea, Mexico, New Zealand, Poland, Russian Federation, South Africa, Spain, United Kingdom, United States
≥60 years
Mean: 69.5 years (SD: 6.5 years)
24,973
12,470
12,503
RSV Lower Respiratory Tract Disease (LRTD)
Medically attended RSV LRTD
Hospitalization for RSV respiratory illness
Severe RSV respiratory illness requiring oxygen/respiratory support
Death due to RSV respiratory illness
Serious adverse events​
Inflammatory neurologic events
Reactogenicity ​(grade ≥3)
GSKLeroux-Roels I, et al. 2022 plus additional unpublished data provided directly from the manufacturer [3,4]
RCT Phase 1/2
Belgium, United States
Vaccine arm (Phase 3 formulation)
Mean: 67.6 years (SD: 5.2 years)
Placebo arm
Mean 68.1 years (SD: 5.7 years)
201 (phase 3 formulation and placebo)
100
101
Serious adverse events​
Inflammatory neurologic events
Reactogenicity ​(grade ≥3)
GSK
**Abbreviations: SD = standard deviation; RCT = randomized controlled trial**Appendix 2. Databases and strategies used for systematic reviewa,b
Appendix 2. Databases and strategies used for systematic review
Database
Strategy**Medline****(OVID)****1946-**
(Respiratory Syncytial Virus Vaccines/ OR ((RSV OR Respiratory Syncytial Virus) AND vaccin*))
AND
(Viral Fusion Proteins/ OR Viral Proteins/ OR (fusion OR prefusion OR pre-fusion OR F protein* OR protein F OR RSV F OR PreF OR pre-f OR F subunit OR RSVpreF OR F vaccin* OR glycoprotein F OR F glycoprotein OR Ad26* OR adenovector 26 OR adenoviral vector* OR adenovirus vector*))
AND
exp adult/ OR (adult* OR elder* OR senior* OR aged OR geriatric*).mp.**Embase****(OVID)****1974-**
(Respiratory Syncytial Virus Vaccine/ OR ((RSV OR Respiratory Syncytial Virus) AND vaccin*))
AND
(Virus Fusion Protein/ OR Viral Protein/ OR (fusion OR prefusion OR pre-fusion OR F protein* OR protein F OR RSV F OR PreF OR pre-f OR F subunit OR RSVpreF OR F vaccin* OR glycoprotein F OR F glycoprotein OR Ad26* OR adenovector 26 OR adenoviral vector* OR adenovirus vector*))
AND
exp adult/ OR (adult* OR elder* OR senior* OR aged OR geriatric*).mp.
NOT pubmed/medline**Cochrane Library**
([mh “Respiratory Syncytial Virus Vaccines”] OR ((RSV OR “Respiratory Syncytial Virus”) AND vaccin*))
AND
([mh “Viral Fusion Proteins”] OR [mh “viral proteins”] OR (fusion OR prefusion OR pre-fusion OR “F protein*” OR “protein F” OR “RSV F” OR PreF OR pre-f OR “F subunit” OR RSVpreF OR “F vaccin*” OR “glycoprotein F” OR “F glycoprotein” OR Ad26* OR “adenovector 26” OR “adenoviral vector*” OR “adenovirus vector*”))
AND
[mh adult] OR (adult* OR elder* OR senior* OR aged OR geriatric*)**CINAHL****(****EbscoHost****)**
((MH “Respiratory Syncytial Virus Vaccines”) OR ((RSV OR “Respiratory Syncytial Virus”) AND vaccin*))
AND
((MH “Viral Fusion Proteins”) OR (fusion OR prefusion OR pre-fusion OR “F protein*” OR “protein F” OR “RSV F” OR PreF OR pre-f OR “F subunit” OR RSVpreF OR “F vaccin*” OR “glycoprotein F” OR “F glycoprotein” OR Ad26* OR “adenovector 26” OR “adenoviral vector*” OR “adenovirus vector*”))
AND
(MH adult+) OR (adult* OR elder* OR senior* OR aged OR geriatric*)
Exclude Medline records**Scopus**
TITLE-ABS-KEY((RSV OR “Respiratory Syncytial Virus”) AND vaccin*) AND TITLE-ABS-KEY(fusion OR prefusion OR pre-fusion OR “F protein*” OR “protein F” OR “RSV F” OR PreF OR pre-f OR “F subunit” OR RSVpreF OR “F vaccin*” OR “glycoprotein F” OR “F glycoprotein” OR Ad26* OR “adenovector 26” OR “adenoviral vector*” OR “adenovirus vector*”) AND TITLE-ABS-KEY (adult* OR elder* OR senior* OR aged OR geriatric*) AND NOT INDEX(medline)**Clinicaltrials.gov**
Respiratory Syncytial Virus Prefusion F Protein OR RSVPreF OR RSVPreF3 OR AD26.RSV.preF| Adult, Older Adult
a. Most recent search conducted January 31, 2023.b. Initial literature search was performed for multiple RSV vaccine products in older adultsTop of Page
							
					
							Last Reviewed:  July 20, 2023						Source: 	National Center for Immunization and Respiratory Diseases
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