Use of Respiratory Syncytial Virus Vaccines in Older Adults

Recommendations of the Advisory Committee on Immunization Practices -- United States, 2023

Michael Melgar, MD; Amadea Britton, MD; Lauren E. Roper, MPH; H. Keipp Talbot, MD; Sarah S. Long, MD; Camille N. Kotton, MD; Fiona P. Havers, MD

Disclosures

Morbidity and Mortality Weekly Report. 2023;72(29):793-801.

Abstract and Introduction

Abstract

Respiratory syncytial virus (RSV) is a cause of severe respiratory illness in older adults. In May 2023, the Food and Drug Administration approved the first vaccines for prevention of RSV-associated lower respiratory tract disease in adults aged ≥60 years. Since May 2022, the Advisory Committee on Immunization Practices (ACIP) Respiratory Syncytial Virus Vaccines Adult Work Group met at least monthly to review available evidence regarding the safety, immunogenicity, and efficacy of these vaccines among adults aged ≥60 years. On June 21, 2023, ACIP voted to recommend that adults aged ≥60 years may receive a single dose of an RSV vaccine, using shared clinical decision-making. This report summarizes the body of evidence considered for this recommendation and provides clinical guidance for the use of RSV vaccines in adults aged ≥60 years. RSV vaccines have demonstrated moderate to high efficacy in preventing RSV-associated lower respiratory tract disease and have the potential to prevent substantial morbidity and mortality among older adults; postmarketing surveillance will direct future guidance.

Introduction

In the United States, respiratory syncytial virus (RSV) causes seasonal epidemics of respiratory illness. Although the COVID-19 pandemic interrupted seasonal RSV circulation, the timing and number of incident cases of the 2022–23 fall and winter epidemic suggested a likely gradual return to prepandemic seasonality.^[1]

Each season, RSV causes substantial morbidity and mortality in older adults, including lower respiratory tract disease (LRTD), hospitalization, and death. Incidence estimates vary widely and are affected by undertesting and potentially low sensitivity of standard diagnostic testing among adults.^[2–5] Most adult RSV disease cases occur among older adults with an estimated 60,000–160,000 hospitalizations and 6,000–10,000 deaths annually among adults aged ≥65 years.^[5–10]

Adults with certain medical conditions, including chronic obstructive pulmonary disease, asthma, congestive heart failure, coronary artery disease, cerebrovascular disease, diabetes mellitus, and chronic kidney disease, are at increased risk for RSV-associated hospitalization,^[11–13] as are residents of long-term care facilities,^[14] and persons who are frail* or of advanced age (incidence of RSV-associated hospitalization among adults increases with age, with the highest rates among those aged ≥75 years).^[6,15] RSV can also cause severe disease in persons with compromised immunity, including recipients of hematopoietic stem cell transplantation and patients taking immunosuppressive medications (e.g., for solid organ transplantation, cancer treatment, or other conditions).^[16,17]

In May 2023, the Food and Drug Administration (FDA) approved the first vaccines for prevention of RSV-associated LRTD in adults aged ≥60 years. RSVPreF3 (Arexvy, GSK) is a 1-dose (0.5 mL) adjuvanted (AS01_E) recombinant stabilized prefusion F protein (preF) vaccine.^[18] RSVpreF (Abrysvo, Pfizer) is a 1-dose (0.5 mL) recombinant stabilized preF vaccine.^[19]

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Next Section

Abstract and Introduction
Methods
Vaccine Efficacy and Safety
Rationale for Recommendations
Recommendations for use of RSV Vaccines in Older Adults
Reporting of Vaccine Adverse Events
Future Research and Monitoring Priorities
References
Sidebar

*Frailty is a multidimensional geriatric syndrome and reflects a state of increased vulnerability to adverse health outcomes. Although there is no consensus definition, one frequently used tool is the Fried frailty phenotype in which frailty is defined as a clinical syndrome with three or more of the following signs or symptoms: unintentional weight loss (10 lbs [4.5 kg] in the past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity.

Table 1. Efficacy of 1 dose of GSK respiratory syncytial virus RSVpreF3 vaccine against respiratory syncytial virus–associated disease among adults aged ≥60 years — multiple countries, 2021–2023
Efficacy evaluation period	Vaccine efficacy against outcome*
Efficacy evaluation period	RSV-associated LRTD^†	RSV-associated medically attended LRTD^§
Season 1^¶	82.6 (57.9–94.1)**	87.5 (58.9–97.6)^††
Season 2^§§	56.1 (28.2–74.4)^††	—^¶¶
Combined seasons 1 and 2 (interim)***	74.5 (60.0–84.5)^†††	77.5 (57.9–89.0)^††

Abbreviations: LRTD = lower respiratory tract disease; RSV = respiratory syncytial virus.
*Manufacturer-calculated efficacy. Includes events >14 days after injection and person-time available from the manufacturer's pivotal phase 3 trial. Estimates adjusted for participant age and region.
^†LRTD defined as two or more lower respiratory symptoms (new or increased sputum, cough, and dyspnea) or signs (new or increased wheezing, crackles or rhonchi detected during 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) for ≥24 hours, including one or more lower respiratory signs, or three or more lower respiratory symptoms for ≥24 hours.
^§Medically attended RSV-associated LRTD defined as LRTD plus attention at one or more inpatient or outpatient health care services. Estimates were not included in per-protocol assessments.
^¶Season 1 vaccine efficacy estimates reflect efficacy against first events occurring during the first complete RSV season for Northern Hemisphere participants and a partial first RSV season for Southern Hemisphere participants (May 2021–April 2022; exact study-defined season dates were site-dependent).
**96.95% CI; the CI for primary trial endpoint was adjusted for multiplicity.
^††95% CI.
^§§Season 2 vaccine efficacy estimates reflect efficacy against first events occurring during the second complete Northern Hemisphere RSV season for Northern Hemisphere participants (August 2022–March 2023; exact study-defined season dates were site-dependent). In addition to Northern Hemisphere participants, Southern Hemisphere participants were also included in these analyses, but this time span reflects an interseason period with low RSV incidence in the Southern Hemisphere.
^¶¶Interim analysis underpowered to estimate efficacy.
***Combined season 1 and 2 (interim) vaccine efficacy estimates reflect efficacy against first events occurring any time during Season 1 or Season 2. The mean time from start to end of efficacy surveillance was approximately 15 months per participant.
^†††97.5% CI; the CI for primary trial endpoint was adjusted for multiplicity.

Table 2. Safety* of 1 dose of GSK respiratory syncytial virus RSVPreF3 vaccine in adults aged ≥60 years — multiple countries, 2021–2023
Safety event	Risk for event
Safety event	RSVPreF3 recipients no./No. (%)^†	Placebo recipients no./No. (%)^§	Relative risk (95% CI)^¶
Serious AE**	549/12,570 (4.4)	540/12,604 (4.3)	1.02 (0.91–1.15)
Severe reactogenicity events^††	37/979 (3.8)	9/976 (0.9)	4.10 (1.99–8.45)
Inflammatory neurologic events^§§	3 events in trials without placebo recipients^¶¶	—^¶¶	—^¶¶

Abbreviations: AE = adverse event; GBS = Guillain-Barré syndrome.
*Includes serious adverse events and severe reactogenicity events observed in GSK's pivotal phase 3 trial (https://pubmed.ncbi.nlm.nih.gov/36791160/) and phase 1/2 trial (https://pubmed.ncbi.nlm.nih.gov/35904987/). Inflammatory neurologic events include those observed across all GSK clinical trials, including an open-label study (https://clinicaltrials.gov/ct2/show/NCT04732871) and a coadministration study (https://clinicaltrials.gov/ct2/show/NCT04841577). Additional data provided by GSK.
^†Represents number of events and percentage of all participants experiencing events observed among RSVPreF3 vaccine recipients across all included trials for each outcome.
^§Represents number of events and percentage of all participants experiencing events observed among placebo recipients across all included trials for each outcome.
^¶Pooled relative risk for events in all included trials for each outcome.
**Serious AEs were defined as any untoward medical occurrence (during 6 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 reaction (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 redness and swelling, grade 3 corresponded to a diameter >3.9" (>100 mm). For fever, grade 3 corresponded to a temperature >102.2°F (>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.
^§§Defined by the Advisory Committee on Immunization Practices Respiratory Syncytial Virus Vaccines Adult Work Group as GBS (including GBS variants), chronic inflammatory demyelinating polyneuropathy, or acute central nervous system inflammation (e.g., transverse myelitis or acute disseminated encephalomyelitis) occurring ≤42 days after vaccination.
^¶¶No inflammatory neurologic events were reported in either the phase 3 or phase 1/2 trials. However, across all RSVPreF3 trials inflammatory neurologic events were reported in three of 17,922 adults vaccinated with RSVPreF3. Events included one case of GBS in an open-label phase 3 clinical trial, and two cases of acute disseminated encephalomyelitis among participants in a randomized phase 3 study of coadministration of RSVPreF3 and standard dose seasonal influenza vaccine. Relative risk could not be calculated because neither trial had a placebo-controlled comparator group.

Table 3. Efficacy of 1 dose of Pfizer respiratory syncytial virus RSVpreF vaccine against respiratory syncytial virus–associated disease among adults aged ≥60 years — multiple countries, 2021–2023
Efficacy evaluation period	Vaccine efficacy against outcome, % (95% CI)*
Efficacy evaluation period	RSV-associated LRTD^†	RSV-associated medically attended LRTD^§
Season 1^¶	88.9 (53.6–98.7)	84.6 (32.0–98.3)
Season 2 (interim)**	78.6 (23.2–96.1)	—^††
Combined seasons 1 and 2 (interim)^§§	84.4 (59.6–95.2)	81.0 (43.5–95.2)

Abbreviations: LRTD = lower respiratory tract disease; LRTI = lower respiratory tract illness; RSV = respiratory syncytial virus.
*Manufacturer-calculated efficacy. Includes events >14 days after injection and person-time available from the manufacturer's pivotal phase 3 trial. Estimates are unadjusted.
^†The RSVpreF trial had two co-primary endpoints, defined as RSV LRTI with two or more lower respiratory signs or symptoms lasting >1 day, and RSV LRTI with three or more lower respiratory signs or symptoms lasting >1 day. Lower respiratory signs and symptoms included new or worsened cough, sputum production, wheezing, shortness of breath, and tachypnea. For RSVpreF estimates in this report, LRTD refers to the RSVpreF trial endpoint of RSV LRTI with three or more lower respiratory signs or symptoms.
^§Medically attended RSV-associated LRTD was defined as LRTD prompting any health care visit (any outpatient or inpatient visit such as hospitalization, emergency department visit, urgent care visit, home health care services, primary care physician office visit, pulmonologist office visit, specialist office visit, other visit, or telehealth contact). Estimates were not included in per-protocol assessments.
^¶Season 1 vaccine efficacy estimates reflect efficacy against first events occurring during the first complete RSV season for Northern and Southern Hemisphere participants (August 2021–October 2022; exact study-defined season dates were site-dependent).
**Season 2 (interim) vaccine efficacy estimates reflect efficacy against first events occurring during the second complete RSV season for Northern Hemisphere participants only (July 2022–January 2023; Southern Hemisphere data not yet available).
^††Interim analysis underpowered to estimate efficacy.
^§§Combined season 1 and 2 (interim) vaccine efficacy estimates reflect efficacy against first events occurring any time during season 1 or season 2. The mean time from start to end of efficacy surveillance was approximately 12 months per participant.

Table 4. Safety* of 1 dose of Pfizer respiratory syncytial virus RSVpreF vaccine in adults aged ≥60 years — multiple countries, 2021–2023
Safety event	Risk for event
Safety event	RSVpreF recipients no./No. (%)^†	Placebo recipients no./No. (%)^§	Relative risk (95% CI)^¶
Serious AE**	792/18619 (4.3%)	749/18334 (4.1%)	1.04 (0.94–1.15)
Severe reactogenicity events^††	36/3673 (1.0%)	24/3491 (0.7%)	1.43 (0.85–2.39)
Inflammatory neurologic events^§§	3/18622 (—)^¶¶	0/18335 (—)	—^¶¶

Abbreviations: AE = adverse events; GBS = Guillain-Barré syndrome.
*Safety events observed in Pfizer's pivotal phase 3 trial (https://pubmed.ncbi.nlm.nih.gov/37018468/) and phase 1/2 trial (https://pubmed.ncbi.nlm.nih.gov/34932102/). There were no additional inflammatory neurologic events observed in any Pfizer clinical trials other than the two trials included. Additional data provided by Pfizer.
^†Represents number of events and percent of all participants experiencing events observed among RSVpreF vaccine recipients across phase 3 and phase 1/2 trials.
^§Represents number of events and percent of all participants experiencing events observed among placebo recipients across phase 3 and phase 1/2 trials.
^¶Pooled relative risk for events in phase 3 and phase 1/2 trials.
**Serious AEs were defined as any untoward medical occurrence (during all available follow-up time [safety follow-up through February 2023] after injection in the phase 3 trial and 60 days for 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 or higher local reaction (injection site pain, redness and swelling) or systemic reaction (fever, fatigue or tiredness, headache, nausea, muscle pain, joint pain, vomiting, diarrhea, and other systemic event) recorded during days 0–7 after vaccination. For injection site redness and swelling, grade 3 corresponded to a diameter >3.9" (>100 mm) from e-diary or severe grade from adverse event case report form. For fever, grade 3 corresponded to a temperature >102°F (>38.9°C) from e-diary or severe grade from adverse event case report form. For all other reactions, grade 3 corresponded to reactions that prevented normal, everyday activities. Grade 4 event corresponded only to a fever >104°F (>40°C).
^§§Defined by the Advisory Committee on Immunization Practices Work Group as GBS (including GBS variants), chronic inflammatory demyelinating polyneuropathy, or acute central nervous system inflammation (e.g., transverse myelitis or acute disseminated encephalomyelitis) occurring ≤42 days after vaccination.
^¶¶Across all RSVpreF clinical trials, including trials other than the phase 3 and phase 1/2 trials summarized in this table, inflammatory neurologic events were reported in three of 20,255 adults ≤42 days after vaccination with RSVpreF (all in the phase 3 trial). The events included GBS, Miller Fisher syndrome (a GBS variant), and undifferentiated motor-sensory axonal polyneuropathy. Relative risk could not be calculated because no events were observed in the placebo-controlled comparator group.

Box. Underlying medical conditions and other factors associated with increased risk for severe respiratory syncytial virus disease
Chronic underlying medical conditions associated with increased risk • Lung disease (such as chronic obstructive pulmonary disease and asthma) • Cardiovascular diseases (such as congestive heart failure and coronary artery disease) • Moderate or severe immune compromise* • Diabetes mellitus • Neurologic or neuromuscular conditions • Kidney disorders • Liver disorders • Hematologic disorders • Other underlying conditions that a health care provider determines might increase the risk for severe respiratory disease Other factors associated with increased risk • Frailty^† • Advanced age^§ • Residence in a nursing home or other long-term care facility • Other underlying factors that a health care provider determines might increase the risk for severe respiratory disease
Abbreviation: RSV = respiratory syncytial virus. *A list of potentially immune compromising conditions is available at https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-who-are-immunocompromised.html. ^†Frailty is a multidimensional geriatric syndrome and reflects a state of increased vulnerability to adverse health outcomes. Although there is no consensus definition, one frequently used tool is the Fried frailty phenotype in which frailty is defined as a clinical syndrome with three or more of the following symptoms present: unintentional weight loss (10 lbs [4.5 kg] in the past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. ^§Among adults aged ≥60 years, RSV incidence increases with advancing age. Although age may be considered in determining an older adult patient's risk for severe RSV-associated disease, there is no specific age threshold at which RSV vaccination is more strongly recommended within the age group of adults aged ≥60 years.