Respiratory Syncytial Virus Vaccination Recommendations for Adults Aged 60 Years and Older: The NeumoExperts Prevention Group Position Paper

Archivos de Bronconeumología 60 (2024) 161–170 w ww.archbronconeumol.org Review Article Respiratory Syncytial Virus Vaccination Recommendations for Adults Aged 60 Years and Older: The NeumoExperts Prevention Group Position Paper Esther Redondoa, Irene Rivero-Calleb,c,d, Enrique Mascaróse, Daniel Oca˜ naf, Isabel Jimenog, Ángel Gild,h, Manuel Linaresi, María Ángeles Onieva-Garcíaj,k, Fernando González-Romol, José Yusted,m, Federico Martinón-Torresb,c,d,∗,♦ aInfectious, Migrant, Vaccines and Preventive Activities Group of SEMERGEN, International Healthcare Centre of the City Council of Madrid, Madrid, Spain bTranslational Paediatrics and Infectious Diseases Section, Paediatrics Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain cGenetics, Vaccines, and Infections Research Group (GENVIP), Healthcare Research Institute of Santiago de Compostela, University of Santiago de Compostela, Santiago de Compostela, Spain dCIBER of Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, Madrid, Spain eHealth Department, Hospital la Fe, Primary Care Centre Arquitecto Tolsá, Valencia, Spain fPrimary Care, Health Care Centre Algeciras, Algeciras, Spain gPrimary Care Health Centre Isla de Oza, Vaccine Responsible of SEMG, Madrid, Spain hPreventive and Public Health, Rey Juan Carlos University, Madrid, Spain iSpecialist in Primary Care and Clinical Microbiology, Infectious Diseases Group SEMERGEN, Fundación io, Madrid, Spain jPreventive Medicine and Public Health Unit, Hospital Universitario Reina Sofía, Cordoba, Spain kMaimonides Biomedical Research Institute of Cordoba (IMIBIC), Spain lClinical Microbiology Department, Hospital Universitario Clínico San Carlos, Madrid, Spain mNational Centre for Microbiology, Instituto de Salud Carlos III, Madrid, Spain a r t i c l e i n f o Article history: Received 18 December 2023 Accepted 9 January 2024 Available online 17 January 2024 Keywords: Respiratory syncytial virus RSV Adult patients Vaccination Recommendations Preventive measures High-risk populations Chronic obstructive pulmonary disease a b s t r a c t Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in adults, particularly older adults and those with underlying medical conditions. Vaccination has emerged as a potential key strategy to prevent RSV-related morbidity and mortality. This Neumoexperts Prevention (NEP) Group scientific paper aims to provide an evidence-based positioning and RSV vaccination recommendations for adult patients. We review the current literature on RSV burden and vaccine development and availability, emphasising the importance of vaccination in the adult population. According to our interpretation of the data, RSV vaccines should be part of the adult immunisation programme, and an age-based strategy should be preferred over targeting high-risk groups. The effectiveness and efficiency of this practice will depend on the duration of protection and the need for annual or more spaced doses. Our recommendations should help healthcare professionals formulate guidelines and implement effective vaccination programmes for adult patients at risk of RSV infection now that specific vaccines are available. © 2024 The Authors. Published by Elsevier Espa˜ na, S.L.U. on behalf of SEPAR. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Introduction Respiratory syncytial virus (RSV) is a common respiratory pathogen that significantly affects vulnerable populations, including infants, older adults, and individuals with chronic medical conditions and immunocompromised status.1More than 158,000 RSV-associated hospitalizations occur annually among adults in the ∗Corresponding author. E-mail address: [email protected] (F. Martinón-Torres). @fedemartinon (F. Martinón-Torres) ♦Web: www.serviciodepediatriasantiago.es/www.genvip.org. EU, 92% of which happen in adults ≥ 65 years.2RSV causes 10,000 deaths among the elderly annually in the US alone.3Furthermore, its mortality rate is comparable to that of influenza.4Given the substantial burden of RSV-related illness in adults,5there is an urgent need to develop effective prevention strategies, particularly through vaccination, and the WHO has emphasised RSV vaccine development as a top priority.6,7 In the last two decades, several vaccine candidates have been designed, targeting young children and older adults.8–10 In 2023, three vaccine formulations designed for older adults successfully completed Phase 3 trials and two already received marketing approval.11 These recent approvals have revolutionised the field and warrant the exploration of potential vaccination strategies https://doi.org/10.1016/j.arbres.2024.01.004 0300-2896/© 2024 The Authors. Published by Elsevier Espa˜ na, S.L.U. on behalf of SEPAR. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/). E. Redondo, I. Rivero-Calle, E. Mascarós et al. Archivos de Bronconeumología 60 (2024) 161–170 and prophylaxis positioning of available products to prevent and control RSV infections. This paper aims to offer evidence-based recommendations for the vaccination of adult patients against RSV. Methods A comprehensive literature review was conducted using electronic databases, including PubMed, Embase, and Cochrane Library until December 2023, to identify relevant studies, clinical trials, and guidelines for RSV infection and vaccination in adults. The search terms included “respiratory syncytial virus”, “adults”, “vaccine”, and related keywords. The selected articles were critically appraised, and data were synthesised to develop evidence-based recommendations. Epidemiology and Clinical Manifestations RSV Epidemiology in Adults RSV has long been recognised as a leading cause of respiratory tract infections in infants and young children. However, recent research has also shed light on the significant burden of RSV infections in adults.5,9 Based on data from the Global Burden of Disease report, which covers 204 countries and territories, the mortality rate for individuals aged 70 years and older in 2019 exceeded that of other age groups. It is worth noting that the mortality rate for people aged 70 years and older compared to infants under 5 years old increased from 0.57 in 1990 to 1.85 in 2019.12 Understanding the epidemiology of RSV in adults is crucial to identifying high-risk populations and implementing effective preventive measures, such as vaccination. RSV peaks are typically observed during the fall and winter, but inter-seasonal RSV activity exists, and its reservoir is exclusively human.13 Occupational exposure is a crucial factor in the epidemiology of RSV in adults. Healthcare and daycare workers are at a higher risk of contracting RSV due to their frequent contact with infected individuals. These occupations play a critical role in the transmission dynamics of RSV, as infected healthcare workers can spread the virus within healthcare settings and vulnerable patient populations.14–16 Adults aged 60 years and older, especially those residing in longterm care facilities or nursing homes, are at increased risk of severe RSV-related illness.17 A recent meta-analysis found that in adults aged 60 years and older, the attack rate for RSV-associated acute respiratory infection was estimated at 1.62%; the hospitalisation attack rate was 0.15%, and the in-hospital case fatality rate (hCFR) was 7.13%.3In Spain, Heppe-Montero et al. estimated an hCFR of 7.91% for patients aged 60 years or older.18 Additionally, age-related comorbidities, such as chronic obstructive pulmonary disease (COPD), congestive heart failure, stroke, chronic kidney disease and diabetes, further heighten the risk of severe RSV infections and the need for hospitalisation.19–23 Furthermore, individuals with compromised immune systems, such as those undergoing immunosuppressive therapy, solid organ transplant recipients, people with HIV infection, and especially those with haematologic malignancies undergoing chemotherapy, are at an elevated risk of severe RSV infections.24 The chronic use of inhaled corticosteroids has also been associated with the increased risk of RSV pneumonia (aOR 2.08 [95% CI: 1.39–3.09]).25 These individuals often experience more prolonged and severe illness and are at an increased risk of complications, including hospitalisation and death.26–28 Complications include bacterial co-infection in up to 29% of adults hospitalised for RSV pneumonia, the most common pathogens being Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus.29 This co-infection rate is even higher than in influenza patients, estimated to occur in 20% of patients.30 RSV infection may also be complicated by cardiovascular events, including acute coronary syndrome, worsening congestive heart failure and arrhythmias in 14–22%.31 Finally, acute functional loss has been associated with a significant shortand long-term reduction in quality of life, which may last for months.8,32 In sum, RSV infections in adults represent a significant public health concern and have a substantial impact on morbidity, mortality, and healthcare utilisation. Older adults, individuals with chronic medical conditions, immunocompromised individuals, and those with occupational exposure face an elevated risk of severe RSV-related illness14–16,18,33–36 Adult RSV Clinical Manifestations RSV infection in adults can present with a wide spectrum of clinical manifestations, ranging from mild respiratory symptoms to severe lower respiratory tract infections. Individual risk factors, comorbidities, and immunological status influence the clinical presentation of RSV in adults.37 The most common clinical symptoms of RSV infection in adults include cough, rhinorrhoea (runny nose), sore throat, nasal congestion, and fever. These symptoms often resemble those of other respiratory viral infections, so clinical diagnosis is challenging without laboratory confirmation. RSV infection may be mistaken for a common cold or influenza, especially during seasonal peaks of respiratory viral activity.38,39 While RSV infections in adults can be self-limiting and resolve without complications, they can also progress to more severe respiratory illnesses, including pneumonia, as a complication of RSV infection that may require hospitalisation.22,40 In some individuals, particularly those with underlying chronic respiratory conditions, RSV infection can lead to exacerbations of pre-existing conditions, such as COPD or asthma.41 In severe cases, RSV infection may result in lower respiratory tract infections, such as bronchiolitis and pneumonia. Bronchiolitis is more commonly observed in infants and young children but can also occur in adults, especially those with compromised lung function or immunocompromised status.42 RSV is also a cause of pneumonia in 49.3% of patients with confirmed RSV infection, primarily in the form of consolidations (23.8%) or ground-glass opacities (19.9%).40 RSV infections in the elderly are frequent and more severe than those with influenza A/B, especially in vulnerable populations, and can result in hospitalisation and, in rare cases, lead to fatal outcomes. These severe outcomes are more likely in individuals with multiple risk factors, advanced age, and significant comorbidities.4,22 In summary, RSV infection in adults has different presentations, ranging from asymptomatic or mild respiratory symptoms to exacerbations of underlying chronic conditions and severe lower respiratory tract infections, such as bronchiolitis and pneumonia. Clinical manifestations can vary widely, and individual risk factors and comorbidities influence the severity of illness. Early identification through efficient diagnostic testing, suitable treatment and specific preventive measures like vaccination are essential in reducing the morbidity and mortality linked to RSV infection in adults. The Virus and Its Diagnosis RSV is a negative-sense, non-segmented RNA virus of more than 15,000 nucleotides. Unlike influenza viruses, it cannot reassort segments, so a large-scale pandemic is unlikely.43 RSV has two major specific antigenic subgroups (A and B) that differ in a number of proteins, but the major genetic diversity lies within the attachment glycoprotein G. However, glycoprotein F is highly conserved between RSVA and RSVB, making it an ideal candidate as a vaccine 162 E. Redondo, I. Rivero-Calle, E. Mascarós et al. Archivos de Bronconeumología 60 (2024) 161–170 antigen, once stabilised in its “pre-fusion” structural conformation, which induces more potent neutralising antibodies by presenting more important epitopes.43,44 Clinical features in adults are not sufficiently helpful in distinguishing RSV from other respiratory agents; therefore, laboratory confirmation may be required. Molecular testing, such as polymerase chain reaction (PCR)-based assays, are rapid, highly sensitive and specific, making them the preferred tool in hospitalised adult patients, particularly when using lower respiratory tract samples. The preferred sample for detecting RSV in adults is a nasopharyngeal swab, but adding additional samples such as saliva, sputum, and serology increases diagnosis accuracy by 2.6-fold.45 Multiplex PCR-based assays enable the simultaneous detection of several respiratory pathogens, albeit at a higher cost. Rapid antigen detection tests (RADTs) provide a quicker, cheaper and more useful point-of-care diagnostic tool, although their sensitivity is less than 10% compared to serological tests and PCR. Immunochromatographic assays targeting RSV F-glycoprotein are used for most RADTs.46 Viral culture is time-consuming and demands trained staff, limiting it to reference labs. Serology offers limited value for immediate diagnosis or patient care, yet when paired with PCR in acute and convalescent phases, its sensitivity is heightened beyond that of viral culture. Whole-genome sequencing and nextgeneration sequencing techniques are presently unavailable for clinical purposes. These techniques are intended mostly for public health research due to their capacity for detecting evolutionary diversity and potential transmission patterns.47 RSV Older Adult Vaccination: Current Status Vaccine Development for RSV Historically, the development of an RSV vaccine has been challenging.48 In light of recent advances in understanding the biology and structure of the RSV virus, particularly the importance of the pre-fusion configuration of the F antigen (Pre-F Ag),49 numerous vaccine candidates have been developed and tested. Each candidate uses a distinct but all use Pre-F Ag. Here, we discuss the current status of RSV vaccine development for the elderly population and highlight key characteristics of various vaccine candidates (Table 1). Subunit Vaccines Subunit vaccines are either proteinor particle-based. Proteinbased vaccines employ purified RSV antigens, including the F or G protein, often formulated with adjuvants to enhance the immune response. Two vaccines have successfully completed Phase 3 trials and have recently been approved for use in older adults (Tables 2 and 3).50,51 The first one, a prefusion F protein RSV vaccine (RSVPreF3, Arexvy, GSK), reported efficacy results in Phase 3 clinical trial in adults ≥ 60 years (AReSVi 006 Study) of 82.6% (95% CI: 57.9–94.1%) for RSV-associated lower respiratory tract disease (LRTD), and 94.1% (95% CI: 62.4–99.9%) for severe RSV-associated LRTD.52 Further analyses stratified by season revealed that one dose of the RSVPreF3vaccine in preventing symptomatic, laboratoryconfirmed RSV-associated LRTD was 82.6% (96.95% CI: 57.9–94.1%) during the first RSV season and 56.1% (95% CI: 28.2–74.4%) during the second full season (Table 3). The cumulative efficacy of a single dose over the two combined seasons was 74.5% (97.5% CI: 60.0–84.5%) in preventing RSV-associated LRTD and 77.5% (95% CI: 57.9–89.0%) in preventing medically attended RSV-associated LRTD. In addition, the vaccine was well tolerated, with no safety concerns.53,54 The second one, a bivalent RSV-A and RSV-B stabilised prefusion F protein vaccine (RSVpreF, Abrysvo, Pfizer) reported efficacy results in Phase 3 clinical trial in adults ≥ 60 years (RENOIR study) of 66.7% (96.66% CI: 28.8–85.8%) for RSV lower respiratory tract illness (LRTI) with at least two signs or symptoms and 85.7% (96.66% CI: 32.0–98.7%) for most severe respiratory disease defined by the presence of three or more symptoms associated with RSV (Table 2).55 Analyses by season reported that one dose of the RSVpreF vaccine prevented symptomatic, laboratory-confirmed RSV-associated LRTD with 88.9% efficacy (95% CI: 53.6–98.7%) during the first RSV season and 78.6% (95% CI: 23.2–96.1%) during the partial second season (Table 3). The efficacy of a single dose over the two combined seasons was 84.4% (95% CI: 59.6–95.2%) in preventing RSV-associated LRTD and 81.0% (95% CI: 43.5–95.2%) in preventing medically attended RSV-associated LRTD. In addition, the vaccine was well tolerated, with no safety concerns.53,54 Nanoparticle-based vaccines use self-assembling nanoparticles presenting key RSV antigens, such as the F glycoprotein or the RSV prefusion-stabilised F protein. They aim to induce a robust neutralising antibody response and have shown promising results in preclinical and early clinical studies.56 IVX-A12, a bivalent vaccine candidate based on nanoparticle technology for treating older adults with RSV and human metapneumovirus (hMPV), started its Phase 3 clinical trial in older adults in June 2023.57 Live Attenuated Vaccines Live attenuated vaccines (LAV) mimic natural infection to induce a strong immune response.58,59 RSV-MinL4-0 (modified polymerase gene), a codon-pair deoptimised LAV, has shown a humoral and cellular immune response similar to wild-type infection in nonhuman primates and has completed Phase 1 trials.60 Chimeric Vaccines Chimeric live virus vaccine candidates express RSV proteins in related attenuated viruses with favourable safety profiles. Unlike vector vaccine candidates, chimeric vaccines show favourable antigen presentation that activates an adaptive immune response. CPI-RSV-F (BLB201), currently in Phase 1 trials, is a chimeric RSV vaccine candidate that includes older adults. Based on an attenuated strain of canine parainfluenza virus expressing the RSV-F protein, a Phase 1 trial is ongoing in the elderly population. The first study cohort showed that 64% of subjects had serum anti-RSV antibody responses above baseline levels.61 Messenger Ribonucleic Acid (mRNA) Vaccines mRNA vaccines have revolutionised vaccine development, exemplified by their successful application in COVID-19 vaccines.62,63 Moderna’s mRNA-1345, an mRNA candidate encoding stabilised RSV pre-F protein, recently reported efficacy results in Phase II + III trial clinical trial in adults ≥ 60 years of 83.7% (95.88% CI: 66.1–92.2%; p < 0.0001) against RSV LRTD as defined by two or more symptoms and 82.4% (96.36% CI, 34.8–95.3) against the disease with at least three signs or symptoms.64 In addition, vaccine efficacy was 68.4% (95% CI, 50.9–79.7) against RSV-associated acute respiratory disease. In general, the vaccine was well tolerated, with no safety concerns. Supported by these results, the company requested the market approval of mRNA-1345 in July 2023. Recombinant Vector Vaccines Recombinant vector vaccines use a genetically modified, replication-deficient virus as a vehicle to elicit both humoral and cellular immune responses by delivering genes encoding specific RSV antigens. Two candidates in clinical development in the elderly population were discontinued due to strategic decisions (Ad26.RSV.preF)65 or failure to meet one of the primary endpoints (MVA-BN-RSV).66 163 E. Redondo, I. Rivero-Calle, E. Mascarós et al. Archivos de Bronconeumología 60 (2024) 161–170 Table 1 Summary of Vaccine Candidates in Development for Older Adults Categorised by Design Strategy.11 Type of vaccine Candidate vaccine | sponsor Antigen Adjuvant Mechanism of action Phase 1 trial (no. participants) Phase 2 trial (no. participants) Phase 3 trial (no. participants) Subunit vaccine VN-0200 | Daiichi Sankyo VAGA-9001a MABH-9002b Protein-based NCT04914520 (48) DPX-RSV |Immunovaccine SHe DepoVax aluminium hydroxide Protein-based: SHe generates a non-neutralising Ab and CD4+ T-cell response NCT02472548 (40) BARS13 | Advaccine G None or cyclosporine A Protein-based: RSV G; immunosuppressant NCT04851977 and ACTRN12618 – 000948291 (60) NCT04681833 (120) RSVPre - F3/GSK3844766A | GSK PreF AS01E Protein-based: Induce immune response with stabilised preF NCT04090658, NCT03814590, and NCT04657198 (1055) NCT04090658 and NCT04657198 (1055) NCT04886596 (25,000) NCT04732871 (1720) NCT05059301 (750) RSVPreF | Pfizer PreF None Protein-based: Induce immune response with stabilised preF NCT03529773 (1235) NCT04785612 (62) NCT04071158 (713) NCT04032093 (1153) NCT05035212 (30,000) IVX-121 | Icosavax Stabilised Pre-F DS-Cav1 None or aluminium hydroxide Particle-based: Presentation of DS-Cav1 on computationally designed VLP generates a neutralising Ab response against preF 2020-003633-38 (90) IVX-A12 (RSV/hMPV) | Icosabax RSV-F/hMPV-F MF59 Particle-based NCT05664334, 120 NCT05903183 (264) Nucleic acid vaccine mRNA-1345 | Moderna PreF None mRNA encodes for a stabilised preF glycoprotein eliciting neutralising antibodies NCT04528719 (100 healthy adults, 300 older adults, 180 women, and 40 children) Phase 2 and 3; NCT05127434 (34,000) NCT05127434 (34,000) NCT05330975 (1350) mRNA LNP | Sanofi PreF None mRNA encodes for a stabilised preF glycoprotein eliciting neutralising antibodies NCT05639894 (790) Live attenuated vaccine RSV-MinL4·0 | Codagenix All viral proteins None L altered for attenuation NCT04295070 (36) Chimeric CPI-RSV-F Vaccine (BLB-201) | Blue Lake Biotechnology Inc. PreF None Parainfluenza virus type 5-vectored live attenuated RSV vaccine NCT05281263 (30) Ab: antibodies; GSK: GlaxoSmithKline; hMPV: human metapneumovirus; mRNA: messenger ribonucleic; RSV: respiratory syncytial virus; SHe: small hydrophobic glycoprotein; VLP: virus-like particle. Positioning and Recommendations for Vaccination in Older Adult Patients The rationale for the recommendations to use RSV vaccines in older adults is based on the known burden of the disease and the evidence of moderate to high efficacy in preventing symptomatic RSV-associated LRTD.52,55 It is important to note that the trials had limited enrollment of individuals at highest risk for RSV disease, and that protection duration and eventual need for additional doses have not yet been established. From an individual protection perspective, healthcare providers should consider individual risk factors, patient preferences, and vaccine characteristics when deciding whether to vaccinate. Post-marketing surveillance and additional studies will provide further information on the safety and effectiveness of RSV vaccines in older adults, which will guide future recommendations.54 Target Population for RSV Vaccination Age-based Indication Strategy The age-based indication strategy involves recommending RSV vaccination for all individuals within a specific age range, regardless of their individual risk levels or underlying conditions. This approach does not require identifying and targeting specific highrisk groups, making it a convenient and efficient strategy. The decision on the age threshold should balance the greatest impact on disease burden and its efficiency.67 164 E. Redondo, I. Rivero-Calle, E. Mascarós et al. Archivos de Bronconeumología 60 (2024) 161–170 Table 2 Efficacy of Currently Licensed RSV Vaccines for Adults 60 Years or Older Based on Phase 3 Trial Results.52,55 Endpoint n/N, Vaccinated group n/N, placebo group Vaccine efficacy (CI), % RSVpreF3 protein vaccine (GSK)52 RSV acute respiratory illness: ≥ 2 respiratory symptoms/signs for ≥ 24 h OR ≥ 1 respiratory symptom/sign + 1 systemic sign for ≥ 24 h 27/12,466 95/12,494 71.7 (56.2–82.3) RSV LRTD: ≥ 2 lower respiratory symptoms/signs for ≥ 24 h including ≥ 1 lower respiratory sign OR ≥ 3 lower respiratory symptoms for ≥ 24 h 7/12,466 40/12,494 82.6 (57.9–94.1) RSV LRTD with ≥ 2 lower respiratory signs or assessed as ‘severe’ by the investigator 1/12,466 17/12,494 94.1 (62.4–99.9) Bivalent RSV prefusion F vaccine (Pfizer)55 RSV LRTI: ≥ 1 respiratory symptom lasting more than 1 day 22/16,306 58/16,308 62.1 (37.1–77.9) RSV LRTI ≥ 2 symptoms: ≥ 2 lower respiratory signs/symptoms lasting more than 1 day 11/16,306 33/16,308 66.7 (28.8–85.8)a RSV LRTI ≥ 3 symptoms: ≥ 3 lower respiratory signs/symptoms lasting more than 1 day 2/16,306 14/16,308 85.7 (37.9–98.4)a a96.66% of confidence interval. CI: confidence interval; LRTD: lower respiratory tract disease; LRTI: lower respiratory tract illness; n: number of events; N: numbers of participants; RSV: respiratory syncytial virus. Table 3 Efficacy of One Dose of Currently Licensed RSV Vaccines for Adults Aged ≥ 60 Years During the First RSV Season, the Second RSV Season and Both Seasons, 2021–2023.53,54 Efficacy evaluation period Vaccine efficacy against outcomeh RSV-associated LRTDaRSV-associated medically attended LRTDb RSVpreF3 protein vaccine (GSK)g,i Season 1c82.6 (57.9–94.1)m87.5 (58.9–97.6)l Season 2 (full)d56.1 (28.2–74.4)l–k Combined seasons 1 and 2 (interim)f74.6 (62.1–83.5)n77.5 (57.9–89.0)l Bivalent RSVpreF vaccine (Pfizer)jRSV-associated LRTD RSV-associated medically attended LRTD Season 1c 88.9 (53.6–98.7)l 84.6 (32.0–98.3)l Season 2 (interim)e78.6 (23.2–96.1)l –k Combined seasons 1 and 2 (interim)f84.4 (59.6–95.2)l 81.0 (43.5–95.2)l CI: confidence interval; LRTD; lower respiratory tract disease; LRTI: lower respiratory tract illness; RSV: respiratory syncytial virus. aFor RSVpreF3 (GSK), LRTD was defined as two or more lower respiratory symptoms (new or increased sputum, cough, and dyspnoea) 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 h, including one or more lower respiratory signs, or three or more lower respiratory symptoms for ≥ 24 h. For RSVpreF (Pfizer) estimates, LRTD refers to the RSVpreF trial endpoint of RSV LRTI with three or more lower respiratory signs or symptoms (see Table 2). bMedically 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. cSeason 1 vaccine efficacy estimates reflect efficacy against first events occurring during the first complete RSV season for Northern Hemisphere participants, partial first RSV season for Southern Hemisphere participants for GSK (May 2021–April 2022; exact study-defined season dates were site-dependent) and complete RSV season Southern Hemisphere participants for Pfizer (August 2021–October 2022; exact study-defined season dates were site-dependent). dSeason 2 vaccine efficacy estimates (GSK) 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. eSeason 2 (interim) vaccine efficacy estimates (Pfizer) 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). fCombined 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 (GSK) or 12 months (Pfizer) per participant. gInterim analysis underpowered to estimate efficacy. hManufacturer-calculated efficacy. Includes events > 14 days after injection and person-time available from the manufacturer’s pivotal Phase 3 trial. iEstimates adjusted for participant age and region. jEstimates are unadjusted. kInterim analysis underpowered to estimate efficacy. l95% CI. m96.95% CI; the CI for the primary trial endpoint was adjusted for multiplicity. n97.5% CI; the CI for the primary trial endpoint was adjusted for multiplicity. High-risk Groups Targeting Strategy The strategy of targeting high-risk groups involves prioritising RSV vaccination for populations at higher risk of severe RSV infection or its complications (Table 4). The main justifications for a strategy of targeting high-risk groups would be: (1) highrisk groups, such as older adults, people with chronic respiratory diseases, immunocompromised individuals and healthcare workers, are more likely to experience severe RSV infection or transmit the virus to vulnerable populations68,69; (2) limited vaccine supply or higher vaccine costs may necessitate prioritising high-risk groups to achieve the greatest public health impact; and (3) targeting high-risk groups allows for a more targeted approach, ensuring that those most susceptible to severe RSV illness are protected.70 Timing and Scheduling of RSV Vaccination Timing of RSV Vaccination: Maximising Protection To ensure maximum protection, it is important to consider the following: •Seasonal outbreaks: RSV infection typically occurs in seasonal outbreaks, with the highest incidence in temperate regions occurring during the autumn and winter months. However, RSV 165 E. Redondo, I. Rivero-Calle, E. Mascarós et al. Archivos de Bronconeumología 60 (2024) 161–170 Table 4 High-risk Groups for RSV Vaccination Recommendations Irrespective of Age. High-risk group Rationale Chronic respiratory disease (COPD/asthma) Higher risk of severe respiratory complications Chronic cardiovascular disease Greater vulnerability to RSV-related morbidity Immunocompromised individuals (including solid organ transplant recipients, HIV) Heightened risk of severe RSV infection, Impaired immune function and susceptibility to RSV Chronic hepatic or renal disease Impaired immune function, greater susceptibility to RSV Diabetes Increased risk of RSV-related illness Neurological impairment Increased risk of RSV-related illness Adults living in nursing homes or long-term care facilities Increase risk of RSV disease COPD: chronic obstructive pulmonary disease; HIV; human immunodeficiency virus; RSV: respiratory syncytial virus. activity can vary geographically. Therefore, local surveillance data should be considered when determining the optimal timing of vaccination. •Ideal timing: Vaccination should ideally be administered before the onset of the RSV season to provide the highest level of protection. However, considering that the currently available vaccines induce protection for at least two seasons,53,54 timing should be as early as possible for those eligible, irrespective of RSV activity. Schedule of RSV Vaccination: Tailoring to Vaccine Type and Individual Factors •Vaccine type: The schedule may vary depending on the specific vaccine. This includes the number of doses required and the interval between doses. Both currently approved RSV vaccines are recommended for administration as a single dose. •Booster doses: Evidence to determine the need for revaccination is not currently available. Integrating RSV Vaccination With Other Vaccines: Optimising Immunisation Coverage •Recommended timing and schedules: RSV vaccination in adults can be seamlessly integrated into routine immunisation schedules by considering the recommended timing and schedules of other vaccines. This allows for efficient and convenient administration of multiple vaccines. •Co-administration with other vaccines: By combining vaccines, individuals can receive multiple vaccinations during a single healthcare visit, reducing the need for additional appointments and associated costs. Both RSVpreF3 (Arexvy, GSK) and RSVpreF (Abrysvo, Pfizer) can be administered concurrently with the seasonal influenza vaccine. RSVpreF3 shows non-inferior immune responses in adults aged 60 and older, but co-administration resulted in numerically lower RSV A and B neutralising titres and influenza A and B hemagglutination inhibition titres, with unknown clinical relevance. RSVpreF, studied in adults aged 65 and older, also demonstrated non-inferior immune responses, but co-administration with adjuvanted influenza vaccine showed similar reductions. RSVpreF requires a two-week interval before tetanus, diphtheria, and acellular pertussis vaccine, and is associated with lower immune responses to pertussis components in co-administration; the clinical relevance remains unknown.50,51 Despite the lack of specific studies, public health authorities can decide to authorise the co-administration of RSV with other vaccines, favouring the opportunity of vaccination against the eventual immunological interference.53,54 NEP Positioning and RSV Prophylaxis Recommendations in Adults The Spanish Neumoexperts Prevention Group (NEP; www.neumoexpertos.org) publishes updated immunisation recommendations to prevent community-acquired pneumonia in adults.70 The proposed vaccine schedule prioritises individual protection to effectively prevent CAP in adults. This schedule is designed to assist healthcare professionals in daily practice by offering the most optimal vaccination recommendations based on the latest evidence. Fig. 1 illustrates the most recent NEP recommendations, including those for RSV vaccination. Concerning RSV prevention, NEP recommends the following measures: 1. Implement infection control measures in healthcare facilities and long-term care settings.71 2. Promote public awareness and education regarding RSV transmission and preventive measures.71 3. Develop and reinforce surveillance systems to monitor community RSV activity and promptly identify outbreaks.71 4. Recommendations for vaccination. From an individual protection perspective, the NEP in Spain recommends RSV vaccination for older adults aged ≥ 60, especially those with chronic pulmonary disease, chronic cardiovascular disease, and other diagnoses or conditions that cause impaired lung function or poor cough strength and stagnation of secretions (extreme obesity or neurological impairments),72 kidney disease, diabetes, immunosuppression, or institutionalised status. Although there are currently two approved vaccines for adults, RSVpreF (Abrysvo, Pfizer) and RSVpreF3 (Arexvy, GSK) that are difficult to compare, given their different clinical studies, varying case definitions, and analysis criteria, both vaccines have demonstrated their efficacy and safety and are recommended in this age group. From a public health perspective, we believe that an agedbased indication is the most recommendable strategy, although the concrete age threshold should be determined balancing the burden of disease prevented and the associated costs of the intervention. The Centres for Disease Control and Prevention (CDC) recommends RSV vaccination for individuals aged ≥ 60 based on shared clinical decision-making between the healthcare provider and the vaccine (Table 5) using either available vaccine.54 In the United Kingdom, the Joint Committee on Vaccination and Immunisation (JCVI) used their modelling to establish the indication for RSV vaccination among older adults aged ≥ 75 (Table 5).73 Irrespective of the age indication, any adult aged over 60 years with specific risk factors for severe RSV disease (Table 4) should be prioritised for vaccination. This strategy likely constitutes a good starting point for any RSV vaccination policy and should be warranted to protect the most vulnerable (Table 6). Also, healthcare workers should be offered RSV vaccination because they are at a higher risk of contracting RSV and to the increased risk of transmitting RSV to their patients.14–16 166 E. Redondo, I. Rivero-Calle, E. Mascarós et al. Archivos de Bronconeumología 60 (2024) 161–170 Fig. 1. Vaccination guide against community-acquired pneumonia in adults caused by vaccine-preventable diseases. CSF: cerebrospinal fluid; IPD: invasive pneumococcal disease. Adapted from Redondo et al.70 Table 5 Official Recommendations on the Use of Licensed RSV Vaccines for Older Adults. Agency/society Age (years) Risk groups Vaccine implementation practice CDC (US)54 ≥ 60 Pulmonary/Heart Disease, Immunosuppression, Institutionalised Arexvy (GSK) and Abrysvo (Pfizer), Shared Clinical Decision-Making JCVI (UK)73 ≥ 75 No specified risk groups Arexvy (GSK) and Abrysvo (Pfizer), Vaccination Programme NEP (SP) ≥ 60 Pulmonary/Heart Disease, Cardiac Disease, Hepatic Insufficiency, Kidney Disease, Diabetes, Immunosuppression, Institutionalised, Neurological Diseases Arexvy (GSK) and Abrysvo (Pfizer), Individual recommendation ≥ 60 Vaccination Programme: at least risk group CDC: Centres for Disease Control and Prevention; JCVI: Joint Committee on Vaccination and Immunisation. 167 E. Redondo, I. Rivero-Calle, E. Mascarós et al. Archivos de Bronconeumología 60 (2024) 161–170 Table 6 Summary of NEP Group Positioning on RSV Vaccination in Older Adults. 1. RSV is a significant cause of respiratory pathology in adults, with a potentially underestimated burden and a significant mortality rate. 2. There are currently two approved vaccines for adults, RSVpreF (Abrysvo, Pfizer) and RSVpreF3 (Arexvy, GSK) that are difficult to compare, given their different clinical studies, varying case definitions, and analysis criteria. Nevertheless, both vaccines have demonstrated their efficacy and safety. 3. The opportunity of co-administration of any available RSV vaccines with other vaccines should be highly considered even in the absence of specific studies. 4. From an individual protection perspective, any individual aged 60 years and older can benefit from vaccination. 5. From a public health perspective, determining the most efficient age recommendation for RSV vaccination in Spain will depend on the applied pharmacoeconomic models/studies. However, it seems reasonable and advisable to at least include it in the adult vaccination schedule for adults aged 60 years and older in the following risk groups: institutionalised individuals, those with chronic cardiovascular, pulmonary or renal diseases, individuals with diabetes mellitus, individuals with immunosuppression and those with neurological impairments. RSV: respiratory syncytial virus. Conclusion Severe RSV disease can have significant consequences in individuals aged ≥ 60 years, particularly those with chronic medical conditions or other risk factors. Vaccination effectively reduces the risk of disease, lessens the severity of illness, and protects vulnerable populations. It is imperative for individuals aged ≥ 60 years to prioritise their health by considering vaccination against RSV as part of their healthy lifestyle and ideal immunisation schedule against pneumonia. Ongoing research, including studies on new vaccine candidates and antiviral therapies, offers hope for the development of even more effective interventions. As vaccines reach the population, implementing positioning strategies, such as improved infection control measures in healthcare facilities and targeted education campaigns, and promoting preventive measures, such as hand hygiene and respiratory etiquette, can help mitigate the impact of RSV on adult health. However, RSV vaccination constitutes a key pillar in the prevention strategy. Continued research, collaboration between scientists, vaccine manufacturers, healthcare professionals and policymakers, and investment in RSV surveillance systems are indispensable to advance our understanding of RSV epidemiology, risk factors, and clinical outcomes in adults and to develop evidence-based interventions to safeguard this vulnerable population. Authors’ Contributions All authors have significantly contributed to the conceptualization and performance of the study. The literature analysis workload has been equally divided among the authors. The elaboration of recommendations has been discussed and agreed among the members, including the multidisciplinary perspective of the NeumoExpert group. All authors have contributed to the critical review of the manuscript. Funding Sources This work was supported by consorcio Centro de Investigacion Biomédica en Red de Enfermedades Respiratorias (CB21/06/00103; FM-T), DIAVIR (Instituto de Salud Carlos III (ISCIII)/DTS19/00049/Cofinanciado FEDER; Proyecto de Desarrollo Tecnológico en Salud), Resvi-Omics (Instituto de Salud Carlos III (ISCIII)/PI19/01039/Cofinanciado FEDER), BI-BACVIR (PRIS-3; Agencia de Conocimiento en Salud (ACIS)—Servicio Gallego de Salud (SERGAS)—Xunta de Galicia; Spain), Programa Traslacional COVID-19 (ACIS—Servicio Gallego de Salud (SERGAS)—XUNTA de Galicia; Spain) and Axencia Galega de Innovacion (GAIN; IN607B 2020/08—XUNTA de Galicia; Spain); and ReSVinext (Instituto de Salud Carlos III (ISCIII)/PI16/01569/Cofinanciado FEDER), Enterogen (Instituto de Salud Carlos III (ISCIII)/PI19/01090/Cofinanciado FEDER), OMI-COVI-VAC (PI22/00406/Cofinanced European Regional Development Fund, Grupos de Referencia Competitiva (IIN607A2021/05) and Axencia Galega de Innovación (GAIN; IN845D 2020/23—Xunta de Galicia; Spain). Conflicts of Interest FM-T has acted as principal investigator in randomised controlled trials of Ablynx, Abbot, Seqirus, Sanofi Pasteur MSD, Sanofi Pasteur, Cubist, Wyeth, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis and GSK, with honoraria paid to his institution. FM-T reports a relationship with GSK Vaccines SRL that includes consulting or advisory. FM-T reports a relationship with Pfizer Inc that includes consulting or advisory. FM-T reports a relationship with Sanofi Pasteur Inc that includes consulting or advisory. FM-T reports a relationship with Janssen Pharmaceuticals Inc that includes consulting or advisory. FM-T reports a relationship with MSD that includes consulting or advisory. FM-T reports a relationship with Seqirus Pty Ltd that includes consulting or advisory. ER has participated in advisory boards, conferences, courses and lectures organised by Sanofi Pasteur, MSD, GSK, Seqirus, Pfizer and AstraZeneca. IRC has participated in advisory boards organised by MSD, GSK, Sanofi and Pfizer. IRC has been involved in clínica trials funded by Ablynx, Abbot, Seqirus, Sanofi Pasteur MSD, Cubist, Wyeth, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis and GSK, alt-hough the funds were paid to the institution. EM has participated in advisory boards by Astra-Zeneca, Boehringer Ingelheim, Esteve, GSK, MSD, Menarini, Mundifarma, Novartis, Orion, Pfizer, Roche, Rovi, Takeda and TEVA. DO has participated in advisory boards from Lilly, Boehringer Ingelheim, Novartis, Pfizer, Takeda, Esteve, Almirall, GlaxoSmithKline, Astra-Zeneca, Chiesi, Mundipharma, Teva, Solvay Pharma, Rovi, Gebro Pharma, Janssen, MSD, Novo Nordisk and Menarini. IJ has participated in advisory boards from Pfizer, Sanofi Pasteur, and conference attendance scholarships paid by Menarini, Esteve. AG has participated in advisory boards by Pfizer, GlaxoSmithKline, Janssen, MSD and Sanofi Pasteur. ML has participated in advisory boards and research projects organised by Pfizer. FGR has participated in advisory boards, conferences, courses and lectures organised by Sanofi Pasteur, MSD, GSK, Pfizer and Moderna. JY received grants from MSD-USA (Merck Investigator Studies Programme), and Pfizer, outside of this work and the funds were awarded to the Institution. JY participated in advisory boards or-ganized by MSD and Pfizer. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgements The authors thank Alfonsina Trento at Medical Statistic Consulting for medical writing services and editorial support in the preparation of this manuscript. References 1. Centers for Disease Control and Prevention (CDC). RSV in older adults and adults with chronic medical conditions. 2022. Available from: https://www.cdc.gov/rsv/high-risk/older-adults.html [updated 15.10.23]. 2. Osei-Yeboah R, Spreeuwenberg P, Del Riccio M, Fischer TK, Egeskov-Cavling AM, Boas H, et al. Estimation of the number of respiratory syncytial virus-associated 168 E. Redondo, I. Rivero-Calle, E. Mascarós et al. Archivos de Bronconeumología 60 (2024) 161–170 hospitalizations in adults in the European union. J Infect Dis. 2023;228: 1539–48. 3. Savic M, Penders Y, Shi T, Branche A, Pircon JY. Respiratory syncytial virus disease burden in adults aged 60 years and older in high-income countries: a systematic literature review and meta-analysis. Influenza Other Respir Viruses. 2023;17:e13031. 4. Ambrosch A, Luber D, Klawonn F, Kabesch M. Focusing on severe infections with the respiratory syncytial virus (RSV) in adults: risk factors, symptomatology and clinical course compared to influenza A/B and the original SARS-CoV-2 strain. J Clin Virol. 2023;161:105399. 5. Korsten K, Adriaenssens N, Coenen S, Butler C, Ravanfar B, Rutter H, et al. Burden of respiratory syncytial virus infection in community-dwelling older adults in Europe (RESCEU): an international prospective cohort study. Eur Respir J. 2021;57:2002688. 6. Giersing BK, Modjarrad K, Kaslow DC, Okwo-Bele JM, Moorthy VS. The 2016 vaccine development pipeline: a special issue from the World Health Organization Product Development for Vaccine Advisory Committee (PDVAC). Vaccine. 2016;34:2863–4. 7. Giersing BK, Modjarrad K, Kaslow DC, Moorthy VS, Committee WHOPDfVA, Committee WHOPDfVPDA. Report from the World Health Organization’s Product Development for Vaccines Advisory Committee (PDVAC) meeting, Geneva, 7–9th Sep 2015. Vaccine. 2016;34:2865–9. 8. Branche AR, Saiman L, Walsh EE, Falsey AR, Sieling WD, Greendyke W, et al. Incidence of respiratory syncytial virus infection among hospitalized adults, 2017–2020. Clin Infect Dis. 2022;74:1004–11. 9. Walsh EE. Respiratory syncytial virus infection: an illness for all ages. Clin Chest Med. 2017;38:29–36. 10. Ruckwardt TJ, Morabito KM, Graham BS. Immunological lessons from respiratory syncytial virus vaccine development. Immunity. 2019;51:429–42. 11. PATH. RSV vaccine and mAb snapshot. 2023. Available from: https://media. path.org/documents/RSV-Snapshot 21SEP2023 clinical-stage HighResolution. pdf [accessed 8.1.24]. 12. Du Y, Yan R, Wu X, Zhang X, Chen C, Jiang D, et al. Global burden and trends of respiratory syncytial virus infection across different age groups from 1990 to 2019: a systematic analysis of the Global Burden of Disease 2019 Study. Int J Infect Dis. 2023;135:70–6. 13. Martinón-Torres F, González-Barcala FJ. Where does respiratory syncytial virus hide? Arch Bronconeumol. 2022;58:298–9. 14. Dare RK, Talbot TR. Health care-acquired viral respiratory diseases. Infect Dis Clin North Am. 2016;30:1053–70. 15. Chughtai AA, Wang Q, Dung TC, Macintyre CR. The presence of fever in adults with influenza and other viral respiratory infections. Epidemiol Infect. 2017;145:148–55. 16. Ling D, Menzies D. Occupation-related respiratory infections revisited. Infect Dis Clin North Am. 2010;24:655–80. 17. Mac S, Shi S, Millson B, Tehrani A, Eberg M, Myageri V, et al. Burden of illness associated with Respiratory Syncytial Virus (RSV)-related hospitalizations among adults in Ontario, Canada: a retrospective population-based study. Vaccine. 2023;41:5141–9. 18. Heppe-Montero M, Gil-Prieto R, Del Diego Salas J, Hernandez-Barrera V, Gil-deMiguel A. Impact of respiratory syncytial virus and influenza virus infection in the adult population in Spain between 2012 and 2020. Int J Environ Res Public Health. 2022;19:14680. 19. Allen JC, Toapanta FR, Chen W, Tennant SM. Understanding immunosenescence and its impact on vaccination of older adults. Vaccine. 2020;38:8264–72. 20. Wyffels V, Kariburyo F, Gavart S, Fleischhackl R, Yuce H. A real-world analysis of patient characteristics and predictors of hospitalization among us medicare beneficiaries with respiratory syncytial virus infection. Adv Ther. 2020;37:1203–17. 21. Mehta J, Walsh EE, Mahadevia PJ, Falsey AR. Risk factors for respiratory syncytial virus illness among patients with chronic obstructive pulmonary disease. COPD. 2013;10:293–9. 22. Falsey AR, Walsh EE, Esser MT, Shoemaker K, Yu L, Griffin MP. Respiratory syncytial virus-associated illness in adults with advanced chronic obstructive pulmonary disease and/or congestive heart failure. J Med Virol. 2019;91:65–71. 23. Hartnett J, Donga P, Ispas G, Vandendijck Y, Anderson D, House S, et al. Risk factors and medical resource utilization in US adults hospitalized with influenza or respiratory syncytial virus in the Hospitalized Acute Respiratory Tract Infection study. Influenza Other Respir Viruses. 2022;16:906–15. 24. Nam HH, Ison MG. Respiratory syncytial virus infection in adults. BMJ. 2019;366:l5021. 25. Luque-Paz D, Tattevin P, Loubet P, Benezit F, Thibault V, Laine F, et al. Chronic use of inhaled corticosteroids in patients admitted for respiratory virus infections: a 6-year prospective multicenter study. Sci Rep. 2022;12:4199. 26. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood. 2011;117:2755–63. 27. Chatzis O, Darbre S, Pasquier J, Meylan P, Manuel O, Aubert JD, et al. Burden of severe RSV disease among immunocompromised children and adults: a 10 year retrospective study. BMC Infect Dis. 2018;18:111. 28. Hynicka LM, Ensor CR. Prophylaxis and treatment of respiratory syncytial virus in adult immunocompromised patients. Ann Pharmacother. 2012;46:558–66. 29. Hedberg P, Johansson N, Ternhag A, Abdel-Halim L, Hedlund J, Nauclér P. Bacterial co-infections in community-acquired pneumonia caused by SARS-CoV-2, influenza virus and respiratory syncytial virus. BMC Infect Dis. 2022;22:108. 30. Qiao M, Moyes G, Zhu F, Li Y, Wang X. The prevalence of influenza bacterial coinfection and its role in disease severity: a systematic review and meta-analysis. J Glob Health. 2023;13:04063. 31. Ivey KS, Edwards KM, Talbot HK. Respiratory syncytial virus and associations with cardiovascular disease in adults. J Am Coll Cardiol. 2018;71:1574–83. 32. Juhn YJ, Wi CI, Takahashi PY, Ryu E, King KS, Hickman JA, et al. Incidence of respiratory syncytial virus infection in older adults before and during the COVID19 pandemic. JAMA Netw Open. 2023;6:e2250634. 33. Zhang S, Wahi-Singh P, Wahi-Singh B, Chisholm A, Keeling P, Nair H, et al. Costs of management of acute respiratory infections in older adults: a systematic review and meta-analysis. J Glob Health. 2022;12:04096. 34. McLaughlin JM, Khan F, Begier E, Swerdlow DL, Jodar L, Falsey AR. Rates of medically attended RSV among US adults: a systematic review and meta-analysis. Open Forum Infect Dis. 2022;9:ofac300. 35. Rafferty E, Paulden M, Buchan SA, Robinson JL, Bettinger JA, Kumar M, et al. Evaluating the individual healthcare costs and burden of disease associated with RSV across age groups. Pharmacoeconomics. 2022;40:633–45. 36. World Health Organization. Progress and future directions of WHO respiratory syncytial virus surveillance – report from the WHO meeting in November 2022. Wkly Epidemiol Rec. 2023;98:159–66. 37. Bruyndonckx R, Coenen S, Butler C, Verheij T, Little P, Hens N, et al. Respiratory syncytial virus and influenza virus infection in adult primary care patients: association of age with prevalence, diagnostic features and illness course. Int J Infect Dis. 2020;95:384–90. 38. Falsey AR, Walsh EE, Osborne RH, Vandendijck Y, Ren X, Witek J, et al. Comparative assessment of reported symptoms of influenza, respiratory syncytial virus, and human metapneumovirus infection during hospitalization and postdischarge assessed by Respiratory Intensity and Impact Questionnaire. Influenza Other Respir Viruses. 2022;16:79–89. 39. Romano CD, Finelli L, Lewis S, Williams V, Martin E, Phillips M, et al. Assessing the patient experience of respiratory syncytial virus infection: development of a patient-reported outcome measure. Health Qual Life Outcomes. 2023;21:20. 40. Lee N, Lui GC, Wong KT, Li TC, Tse EC, Chan JY, et al. High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections. Clin Infect Dis. 2013;57:1069–77. 41. Tseng HF, Sy LS, Ackerson B, Solano Z, Slezak J, Luo Y, et al. Severe morbidity and shortand midto long-term mortality in older adults hospitalized with respiratory syncytial virus infection. J Infect Dis. 2020;222:1298–310. 42. Ryu JH, Azadeh N, Samhouri B, Yi E. Recent advances in the understanding of bronchiolitis in adults. F1000Research. 2020:9. 43. Kaler J, Hussain A, Patel K, Hernandez T, Ray S. Respiratory syncytial virus: a comprehensive review of transmission, pathophysiology, and manifestation. Cureus. 2023;15:e36342. 44. Taleb SA, Al Thani AA, Al Ansari K, Yassine HM. Human respiratory syncytial virus: pathogenesis, immune responses, and current vaccine approaches. Eur J Clin Microbiol Infect Dis. 2018;37:1817–27. 45. Ramirez J, Carrico R, Wilde A, Junkins A, Furmanek S, Chandler T, et al. Diagnosis of respiratory syncytial virus in adults substantially increases when adding sputum saliva, and serology testing to nasopharyngeal swab RT-PCR. Infect Dis Ther. 2023;12:1593–603. 46. Talbot HK, Belongia EA, Walsh EE, Schaffner W. Respiratory syncytial virus in older adults: a hidden annual epidemic. Infect Dis Clin Pract. 2016;24:295–302. 47. Griffiths C, Drews SJ, Marchant DJ. Respiratory syncytial virus: infection detection, and new options for prevention and treatment. Clin Microbiol Rev. 2017;30:277–319. 48. Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine12. Am J Epidemiol. 1969;89:422–34. 49. McLellan JS, Chen M, Leung S, Graepel KW, Du X, Yang Y, et al. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science. 2013;340:1113–7. 50. EMA-EPAR. Abrysvo Respiratory syncytial virus vaccine (bivalent, recombinant). 2023. 51. EMA-EPAR. Arexvy (Recombinant respiratory syncytial virus pre-fusion F protein, adjuvanted with AS01E. 2023. 52. Papi A, Ison MG, Langley JM, Lee DG, Leroux-Roels I, Martinon-Torres F, et al. Respiratory syncytial virus prefusion f protein vaccine in older adults. N Engl J Med. 2023;388:595–608. 53. Melgar M. Updated Evidence to Recommendation Framework: respiratory syncytial virus (RSV) in adults [Presentation slides]. Advisory Committee on Immunization Practices meeting; June 21. Atlanta, GA; 2023. 54. Melgar M, Britton A, Roper LE, Talbot HK, Long SS, Kotton CN, et al. Use of respiratory syncytial virus vaccines in older adults: recommendations of the advisory committee on immunization practices – United States, 2023. MMWR Morb Mortal Wkly Rep. 2023;72:793–801. 55. Walsh EE, Perez Marc G, Zareba AM, Falsey AR, Jiang Q, Patton M, et al. Efficacy and safety of a bivalent RSV prefusion F vaccine in older adults. N Engl J Med. 2023;388:1465–77. 56. Swanson KA, Rainho-Tomko JN, Williams ZP, Lanza L, Peredelchuk M, Kishko M, et al. A respiratory syncytial virus (RSV) F protein nanoparticle vaccine focuses antibody responses to a conserved neutralization domain. Sci Immunol. 2020;5:eaba6466. 57. Icosavax Initiates Phase 2 Trial of IVX-A12 Against RSV and hMPV in Older Adults [press release]. June 20, 2023. 58. Pollard AJ, Bijker EM. A guide to vaccinology: from basic principles to new developments. Nat Rev Immunol. 2021;21:83–100. 59. Karron RA, Atwell JE, McFarland EJ, Cunningham CK, Muresan P, Perlowski C, et al. Live-attenuated vaccines prevent respiratory syncytial virus-associated illness in young children. Am J Respir Crit Care Med. 2021;203:594–603. 169