Clinical Microbiology and Infection 29 (2023) 1538e1550

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Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

Narrative review

Respiratory syncytial virus in adults with comorbidities: an update

on epidemiology, vaccines, and treatments

1, 4, Nathan Peiffer-Smadja 1, 5,
Donia Bouzid 1, 2, Benoit Visseaux 3, Valentine Marie Ferre
Quentin Le Hingrat 1, 4, Paul Loubet 6, 7, *
1)
Universit

e Paris Cit

e, INSERM UMR1137, IAME, F-75018, Paris, France
2)
AP-HP Nord, Emergency Department, Bichat-Claude Bernard University Hospital, Paris, France
3) ^ne, France
Laboratoire Cerba, Infectious Diseases Department, Saint Ouen l’Aumo
4)
AP-HP Nord, Infectious Diseases Department, Bichat-Claude Bernard University Hospital, Paris, France
5)
AP-HP Nord, Virology Department, Bichat-Claude Bernard University Hospital, Paris, France
6)
Universit

e de Montpellier, VBMI, Inserm U1047, Nîmes, France
7)
Department of Infectious and Tropical Diseases, CHU Nîmes, Universit

e de Montpellier, Nîmes, France

a r t i c l e i n f o a b s t r a c t

Article history: Background: Respiratory syncytial virus (RSV) is widely known as a frequent cause of respiratory distress
Received 25 May 2023 among adults, particularly in older people. Recent years have witnessed several improvements in res-
Received in revised form piratory virus detection, leading to more questions about therapeutic management strategies.
19 August 2023
Objectives: This narrative review focuses on the RSV burden in older people and adults with risk factors
Accepted 30 August 2023
Available online 2 September 2023
and provides an update on the main recent developments regarding managing this infection.
Sources: A comprehensive PubMed search was conducted till August 2023 to identify studies on RSV
Editor: R. Chemaly among the adult population. We included observational studies, RCTs on vaccines, and different therapies.
Content: This review should give clinicians an overview of RSV epidemiology and burden among older
Keywords: people and adults with pre-existing risk factors, the most recent randomized clinical trials on RSV
RSV vaccines, and the existing data on the different therapeutics existing and under development.
RSV treatment Implications: There is a growing body of evidence on RSV burden in adults. The landscape of preventive
RSV vaccine and curative treatments is quickly evolving. Donia Bouzid, Clin Microbiol Infect 2023;29:1538
© 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction monitoring and new management strategies for all viral respiratory
infections. Several RSV vaccine candidates for older adults are under
Respiratory syncytial virus (RSV) is among the leading causes of clinical development [6]. Today, the primary approach to treating
hospitalization for acute respiratory distress in infants and young RSV involves providing supportive care, and the sole approved
children [1]. However, it is also a significant threat to adults over 60. antiviral treatment for RSV disease continues to be ribavirin [7].
The tally of RSV-attributable deaths is much higher in older adults This narrative review focuses on the RSV burden in older people
than in infants [2]. In the United States, 6000e10000 annual deaths and adults with risk factors and provides an update on the main
are attributable to RSV in older people [3]. In the United Kingdom, recent developments regarding managing this infection. Thus, we
8482 deaths are caused by RSV each year, mainly in adults aged describe the epidemiology and burden of RSV infections and
over 65 years [4]. discuss existing preventive and therapeutic approaches as well as
The COVID-19 pandemic has changed multiple aspects of viral those in development.
respiratory infection management. It has also modified the usual
seasonality of respiratory viruses, affecting testing strategies [5]. Methods
These epidemiological changes highlight the need for biological
A comprehensive PubMed search was conducted from August
2022 to August 2023 to identify studies on RSV among the adult
* Corresponding author. Paul Loubet, Department of Infectious and Tropical
population. We used the following MeSH terms and keywords:
Diseases, CHU Nîmes, Universite
de Montpellier, Nîmes, France. ‘respiratory syncytial virus’, ‘RSV’, ‘RSV epidemiology’, ‘RSV treat-
E-mail address: paul.loubet@chu-nimes.fr (P. Loubet). ment’, ‘RSV vaccine’, ‘RSV infection’, ‘RSV in adults’, and ‘RSV RCT’.

https://doi.org/10.1016/j.cmi.2023.08.028
1198-743X/© 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
 D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550 1539

We mainly focused our review on studies published since 2020 to ICU with RSV infection with those with influenza infection. Their
provide the most recent information and developments. We also findings also indicated that patients affected by RSV had a higher
searched clinicaltrials.gov for all registered on-going trials of RSV occurrence of pre-existing medical conditions (60% vs. 40%,
vaccines, monoclonal antibodies, and other antivirals. p < 0.001) and were more immunocompromised (35% vs. 26%, p
0.02). However, their in-hospital mortality rate was comparable
RSV overall burden (24% vs. 26%; aOR, 0.80; 95% CI: 0.49e1.30) (Table 1). A recent study
of 302 adults aged 60 years hospitalized with laboratory-
RSV holds the distinction of being the most frequently detected confirmed RSV infection in the United State found that RSV-
virus in lower respiratory tract infections (LRTI) among infants, and associated hospitalization resulted in acute and prolonged func-
its recognition as the primary cause of bronchiolitis dates back to tional loss. Indeed, 14% of patients required a higher level of care at
1957 [8]. Re-infection is common, affecting up to 10% of young discharge, and around 32% experienced decreased instrumental
adults yearly, and usually manifests with only mild symptoms [9]. activities of daily living and activities of daily living scores 6 months
However, RSV was not recognized as a potential agent for severe after hospitalization [18]. These findings highlight that the burden
infection in older adults until the late 1960s, when outbreaks of RSV extends beyond its mortality and affects the daily activities
occurred in long-term care facilities and health authorities started of patients who have recovered from their viral infection.
advocating for surveillance among this population [10,11]. The high The emergence of SARS-CoV-2 modified the circulation of other
burden of RSV infection in older people has been extensively respiratory viruses because of the implementation of non-
documented over the last few years. For instance, the RESCEU pharmaceutical interventions (NPIs), including hand hygiene, face
observational cohort study conducted in Antwerp (Belgium), Ox- masks, travel restrictions, and social distancing [19]. An Italian
ford (United Kingdom), and Utrecht (The Netherlands) included study evaluating the prevalence of different respiratory viruses
1040 patients, with a median age of 75, tested at home within the from January 2017 to May 2021 revealed that overall multiplex PCR
72 hours after the first symptom of acute respiratory tract infection positivity (excluding SARS-CoV-2) declined from 14.6% in the pre-
(ARTI). RSV illness incidence was 4.2% during the 2017e2018 COVID-19 era to 2.7% after the COVID-19 pandemic (p < 0.0001).
epidemic and 7.2% during the 2018e2019 epidemic [10]. The find- This sharp decline also concerned RSV, whose positivity rate
ings from this cohort indicate that RSV infections among older dropped from 5% to 0.14% over the same period (p < 0.0001) [20].
adults living in communities are typically mild and do not require Several surveillance programmes worldwide have also described
extensive intervention. In comparison with influenza-associated this halted circulation of RSV in the months after the introduction
ARTI, RSV-ARTI resulted in fewer medical appointments (31% vs. of SARS-CoV-2 [5]. During the COVID-19 pandemic, inter-seasonal
60%, p 0.006) and led to fewer prescriptions for antibiotics (6% vs. RSV circulation was observed worldwide, a pattern that not all
31%, p 0.004) [10]. However, other cohorts in different regions and winter-associated viruses could achieve, with peaks of infections
settings reported slightly higher hospitalization rates and more during year periods when RSV does not usually circulate [21e23].
severe diseases when patients required hospitalization. Thus, in a This unusual RSV circulation was concurrent with the easing of NPI
British study, RSV was estimated to account for 71 (95% confidence phases worldwide [5,22]. As shown for influenza, the reduced RSV
interval [CI] 52e90) hospitalizations for ARTI per year and per circulation led to lower genetic diversity as local epidemics ended
100 000 adults aged 65e74 and 251 (95% CI: 186e316) hospitali- [24]. For instance, in Australia, a significant collapse in the number
zations per year per 100 000 adults over 75 years old [12]. In a of lineages circulating was observed in the COVID-19 era. This
group of patients from the United States, 21% of those who were coincided with the emergence of two distinct but phylogenetically
hospitalized because of an RSV infection (of a total of 664 patients) related RSV-A lineages associated with summer outbreaks in the
needed assistance from ventilators, whereas 18% had to be placed region [23]. After this substantial decline in RSV prevalence, sig-
in the intensive care unit (ICU) [13]. In a recent French study, the nificant outbreaks of the virus have been noted in numerous
mortality rate within the hospital was recorded at 6.6% (77 of 1168), countries, coinciding with the relaxation of NPIs, particularly dur-
whereas for patients who required ICU admission, the mortality ing the winter of 2022e2023. It has been hypothesized that the
rate was higher, at 12.8% (37 of 288). Furthermore, the factors reduced circulation of respiratory viruses during the early days of
linked with the need for invasive mechanical ventilation included the COVID-19 pandemic might have increased the pool of suscep-
chronic heart conditions (adjusted OR [aOR] ¼ 1.98 [1.20e3.26]), tible individuals, facilitating their transmission. An additional hy-
respiratory failure (aOR ¼ 2.83 [1.67e4.80]), and co-infection pothesis suggests that during the resurgence phase, the presence of
(aOR ¼ 2.62 [1.60e4.30]) [14]. A retrospective cohort comparing various respiratory viruses might have led to intensified in-
the clinical patterns of hospitalized patients infected with influenza teractions among these viruses, potentially causing elevated in-
(n ¼ 479) and with RSV (n ¼ 79) in Switzerland reported an stances of viral co-infections or super-infections. Concerning these
increased risk of ICU admission or death among patients with RSV viral interactions, their impacts can be either cumulative or sub-
(19% vs. 10% for patients with influenza, p 0.0024) [15]. In the latter tractive, as evidenced by findings from experimental models,
study, all patients with symptoms and signs of ARTI and whose clinical instances, and/or epidemiological information [25].
condition required hospital admission were tested by a combined
RT-PCR detecting both influenza viruses and RSV. A French study Older patients (>60 years)
included adults hospitalized with influenza-like illness in five
university hospitals over two consecutive winter seasons between The first study focusing on RSV burden among older people and
2017 and 2019. The primary observations revealed that patients high-risk groups (chronic heart or lung disease) was published by
admitted to the hospital because of RSV were of advanced age Falsey et al. [8]. It was conducted in 2005, and a total of 608 healthy
compared with those with influenza (average age 73.0 years vs. older patients and 540 high-risk adults were included. Among the
68.8 years, p 0.015). In addition, the RSV patients exhibited a participants in the prospective cohorts, 102 individuals were
greater prevalence of comorbidities, including chronic respiratory diagnosed with RSV infection, whereas 142 hospitalized patients
or cardiac conditions (52% vs. 39%, p 0.012 and 52% vs. 41%, p 0.039, were also found to have RSV infection. RSV infection developed
respectively), and a lengthier hospitalization period (median stay of annually in 3e7% of healthy older patients and 4e10% of high-risk
8 days vs. 6 days, p < 0.001) [16]. A study by Coussement et al. [17] adults. The use of medical care was significantly higher in the high-
also compared the patterns and outcomes of adult patients in the risk group: 23% called the doctor, 29% visited a physician, 9% visited
Table 1

1540
Studies on RSV infection's features, therapeutics, and randomized clinical trials on RSV vaccines for adults

Study and aim Design Sample size Outcomes/measures Results

RSV infection's features

1 Godefroy et al. Open For Infect. Dis 2020 Retrospective multi-centric 4 centres AP-H N ¼ 12 443 5.7% RSVþ (n ¼ 701) 12% In-hospital mortality RSV alone vs. co-infection Crude mortality:
The aim was to describe the epidemiology Marseille. All adult patients hospitalized bacterial co-infection (n ¼ 85) 4.9% vs. 12.9%. In 65 years. Age and length
of bacterial co-infection in patients with with RSV infection February 2014eApril of stay adjusted Cox model: HR ¼ 2.9 (95%
RSV-ARI 2019 CI: 1.3e6.6)
2 Tseng et al. J Infect Dis 2020 This observational, retrospective, cohort 664 patients aged 60 years Outcomes of hospitalization included Baseline chronic diseases were prevalent
The aim was to describe the clinical study was conducted at KPSC, an integrated hospitalized with RSV length of stay, occurrence of (all >30%); 66% developed pneumonia, 80%
epidemiology and outcomes among a large healthcare system that provides complications, use of respiratory of which were radiographically confirmed.
cohort of older adults hospitalized with RSV comprehensive prepaid health services for support, ICU admission, re-admission, Very severe tachypnoea (26 breaths/
infection in the United States 4.4 million members cared for at 15 large, use of vasopressors, mortality, and minute) was common (56%); 21% required
community-based hospitals that are owned exacerbation of chronic conditions, ventilator support and 18% were admitted
and operated by KPSC discharge location, and healthcare to intensive care unit. Mortality during
utilization after discharge hospitalization was 5.6% overall (4.6% in 60
e74-year olds and 6.1% in 75 year olds).

D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550

Cumulative mortality within 1, 3, 6, and
12 months of admission was 8.6%, 12.3%,
17.2%, and 25.8%, respectively
3 Descamps et al. Eur Resp J 2021 Data FLUVAC Prospective multi-centric 5 N ¼ 1422 8% RSV n ¼ (108)/31% In-hospital outcome: pneumonia, RSV vs. influenza older: 73 ± 13 vs.
The aim was to describe in/out-hospital centres: Paris (Cochin, Bichat) Rennes influenza (n ¼ 437). At least one respiratory failure, ARDS, or acute heart 69 ± 17 years. Chronic respiratory disease:
outcomes of RSV infection among adults (Pontchaillo) Montpellier, Lyon (Edouard respiratory virus was detected in 53% of failure, or LOS 7 days or ICU or 52% vs. 39%. At least one complication: 58%
hospitalised with ILI (according to European Herriot) Winter seasons 2017/2018 and adults hospitalized with ILI symptoms mechanical ventilation In-hospital vs. 47%. Respiratory failure: 31% vs. 16%.
Centre for Disease Prevention and Control 2018/2019 death Post-discharge outcome: 30- and Acute heart failure:15% vs. 8%. In-hospital
(ECDC) definition) and to compare them to 90-day all-cause mortality or 90-day re- death: 3%
patients admitted for influenza admission
4 De Francesco et al. Int J Envi Res. 2021 Retrospective, single centre. All adults with Samples tested other than SARS-CoV2: Positivity rate RSV pre-pandemic: 238/3240 (7.3%). During
The aim was to evaluate the prevalence of respiratory symptoms and tested for re 10 121 vs. 2362. Positive: 1475 (15%) vs. the pandemic: 10/734 (1.4%). The overall
respiratory viruses pathogens January 2017eFebruary 2020 vs. 63 (3%) test positivity for all respiratory viruses was
March 2020-May 2021 lower during the pandemic than in the
previous years (2.7% vs. 14.6%, p < 0.0001)
5 Almeida et al. Infection 2021 Retrospective, multi-centric: Italy, Portugal, 984 patients n ¼ 447 in 2017e2018 In-hospital death IMV NIV RSV: n ¼ 207 (21%), influenza: n ¼ 557
The aim was to compare the clinical severity and Cyprus n ¼ 537 in 2018e2019 (57%). Crude OR (RSV) death: 1.2 (0.7e1.9);
of LRTIs caused by Influenza and RSV Adult inpatients with positive PCR for IMV: 0.6 (0.3e1.2) NIV: 1.5 (1.0e2.2),
influenza or RSV (excluding co-infections) adjusted OR (H1N1) death: 2.0 (1.2e3.4);
Adult inpatients with positive PCR for IMV: 5.1 (3.0e8.5)
influenza or RSV (excluding co-infections)
October 2017eApril 2018 and October 2018
eApril 2019
6 Oh et al. The Lancet 2021 Germany 3580 specimens from patients with ARI 2017: n ¼ 287/3876 (7%)
The aim was to report effect of COVID-19 Nationwide German ARI Sentinel 2018: n ¼ 180/4797 (4%)
NPI on other viruses surveillance data 2019: n ¼ 285/3150 (9%)
2017e2019 and JanuaryeSeptember 2020 2020: n ¼ 152/3580 (4%)
2017e2019 and JanuaryeSeptember 2020
7 García-Arroyo et al. Inf Other Resp Vir 2021 Spain N ¼ 59 579 specimens 2020: n ¼ 66 616 RSV 1997e2019: n ¼ 6160 (28%)
The aim was to describe the distribution of Retrospective, single centre specimens 2018: n ¼ 389/4883 (21%)
respiratory viruses January 1997eMarch 2020 2018: n ¼ 389/4883 (21%)
2018: n ¼ 389/4883 (21%)
2018: n ¼ 389/4883 (21%)
10 Chorazka et al. PLOS ONE 2021 Switzerland 1983 patients tested, RSVþ: n ¼ 79 (4%), ICU admission (need for ventilatory or RSV vs. Infl:
The aim was to compare clinical burden of Retrospective; two centres Inflþ: n ¼ 479 (24%) vasopressor support) and/or in-hospital More infiltrate on chest X-ray: 46% vs. 30%,
RSV and influenza Adult patients hospitalized for ARI with a death within 7 days after hospital p 0.007
lab confirmed influenza or RSV admission ICU adm or death within 7 days: 19% vs.
Seasons 2017/2018 or 2018/2019 Cardiopulmonary/vascular events 10%, p 0.024
Antibiotic treatment ICU adm within 7 days: 15% vs. 8%, p 0.035
Discharge to nursing home Similar for other characteristics and
30-day re-admission outcomes
30-day all-cause mortality
 Similar for other characteristics and
outcomes
11 Korsten et al. Eur Respir J 2021 The RESCEU older adult study is an N ¼ 1040 patients Severe dis: hospitalization within RSV illness incidence was 22 of 527 (4.2%)
The aim was to assess the incidence and international, prospective, observational Median age: 75 years old 28 days after ARTI onset and 37 of 513 (7.2%) in the respective
severity of RSV infection in community- cohort study conducted in Antwerp Moderate dis: any medical attendance seasons. RSV-ARTI required less medical
dwelling older adults aged 60 years and (Belgium), Oxford (United Kingdom) and or new or increased used of inhaled attendance compared with influenza ARTI
above in its older adult cohort study Utrecht (The Netherlands) across two respiratory medication, antibiotics, (31% vs. 60%, p 0.006) and fewer antibiotic
consecutive RSV seasons (2017e2018 and antivirals, or corticosteroids prescriptions (6% vs. 31%, p 0.004).
2018e2019) Symptom duration for RSV-ARTI averaged
19 days and was significantly longer
compared with other infections (19 vs.
12 days, p 0.006), but was similar to
influenza ARTI (19 vs. 18 days, p 0.53)
12 Coussement et al. Chest 2022 Retrospective multi-centre matched cohort N ¼ 618 309 RSV/309 influenza Characteristics: in-hospital mortality RSV vs. Influenza More underlying chronic
The aim was to compare the characteristics 15 France/2 Belgium Age at admission RSV: 67 ± 15 Inf: during the ICU stay Length of hospital respiratory condition (60% vs. 40%;
and outcomes of adult patients in the ICU Adults with RSV during ICU stay matched to 65 ± 16 and ICU stay Respiratory support p < 0.001) More immunocompromised
with RSV infection with those with patients with influenza November 2011 (35% vs. 26%) Similar In-hospital mortality
influenza infection eApril 2018 (24% vs. 26%; aOR*, 0.80; 95% CI: 0.49e1.30)

D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550

50% endotracheal intubation and invasive
ventilation during ICU
13 Sberna et al. Int. J. Environ. Res. Public Retrospective multi-centric in the Lazio 633 NPSs subjected to molecular Positivity rate In 2019, in 144 NPSs, the more represented
Health 2022 region, Italy Adults hospitalized patients diagnosis for CRPs by multiplex PCR CRPs were rhinovirus/enterovirus (7.6%)
The aim was to provide a descriptive with ILI during the fall seasons of the past assay and influenza A/B (4.2%). In 2020, 55 (21.6%)
analysis of CRPs detected in NPSs 3 years, 2019e2021 of 255 NPSs resulted positive for SARS-CoV-
2 and, except for one case of Legionella
pneumophila, the CRPs detected were
exclusively rhinovirus/enterovirus (4.7%). In
2021, among 234 NPSs, 25.6% resulted
positive for SARS-CoV-2, 14.5% for
respiratory syncytial virus (RSV), and 12.8%
for rhinovirus/enterovirus
14 Choi et al. Inf Other Resp Vir 2022 This is a prospective surveillance for RSV 756 adults 18 years of age admitted to The primary outcome for this study was The mean total cost of hospitalization was
The aim was to evaluate the costs of RSV- infection was conducted over 3 RSV seasons three hospital systems in New York the cost of RSV-associated $8403 (95% CI: $7240e$9741). The annual
associated hospitalization in adult patients at three hospital systems during 2 RSV seasons who were RSV- hospitalization from admission to United States cost was estimated to be $1.2
with laboratory-confirmed, community- positive by PCR and had more than or discharge or in-hospital death (95% CI: 0.9e1.4) billion
onset RSV equal to two acute respiratory infection
symptoms or exacerbation of
underlying cardiopulmonary disease
15 Sharp et al. Inf Other Resp Vir 2022 UK Retrospective Adults 65 years Hospital 4255 K admissions 109 K lab records Time series for actual and expected Seasonal annual average of admissions:
The aim was to estimate incidence of Episode Statistics database, August 2010 39 219 RSV cases weekly admissions weekly admissions RSV: 71/100 000 (95% CI 52e90) in 65
hospital admission due to respiratory eJuly 2017 attributable to each pathogen e74 years; 251 (186e316) in 75þ
illnesses attributable to RSV Rate of hospital admissions Pneumococus: 448 (310e587); 1010 (527
e1493), respectively
Influenza A: 45 (34e56); 119 (82e155)
Parainfluenza: 50 (7e93); 157 (3e310)
16 Chow et al. Nat Rev Microbiol 2022 Through the Seattle Flu Study (a community Data from different surveillance system Outbreaks description Global influenza virus activity remained
The aim of was to summarize the surveillance consortium in the Seattle, WA, low during the 2021e2022 influenza
epidemiology of common respiratory virus USA, metropolitan area) community season, with low influenza virus numbers
infections and then focus on the effect of respiratory virus detection was monitored (as well as of most viruses) detected overall
SARS-CoV-2 and the use of NPIs in year-round in northern temperate zone countries and
modifying the circulation, clinical burden countries in the tropics and subtropics.
and evolution of endemic respiratory virus Inter-seasonal RSV circulation has occurred
infections during the COVID-19 pandemic, with
uncharacteristic peaks during times of the
year not typical of RSV seasonality
17 Eden et al. Nat Commun 2022 An observational study with the description NA Genomic sequencing of RSV Genomic sequencing revealed a major
The aim was to this work underscore the of the epidemiology of RSV in Australia reduction in RSV genetic diversity after
urgent need for on-going surveillance for following the emergence of SARS-CoV-2
(continued on next page)

1541
Table 1 (continued )

1542
Study and aim Design Sample size Outcomes/measures Results

RSV, influenza virus and other major with large scale outbreaks of disease COVID-19 emergence with two genetically
respiratory pathogens to examine changes occurring out-of-season during the summer distinct RSV-A clades circulating cryptically
in their genetic diversity, particularly of 2020e21 associated to genomic
towards informing vaccine compositions sequencing of the RSV samples
18 Branche et al. CID 2022 A prospective, population-based, 1099 adults hospitalized with RSV Population-based RSV incidence rates Annual incidence during three seasons
The aim was to estimate incidence of RSV surveillance study of hospitalized adults ranged from 44.2 to 58.9/100 000. Age-
hospitalization among adults overall and aged 18 years residing in the surveillance groupespecific incidence ranged from 7.7
those with specific comorbidities area with 2 ARI symptoms or exacerbation to 11.9/100 000, 33.5 to 57.5/100 000, and
of underlying cardiopulmonary disease 136.9 to 255.6/100 000 in patients ages 18
were screened during the 2017e2018, 2018 e49, 50e64, and 65 years, respectively.
e2019, and 2019e2020 RSV seasons Incidence rates in patients with chronic
obstructive pulmonary disease, coronary
artery disease, and congestive heart failure
were 3e13, 4e7, and 4e33 times,
respectively, the incidence in patients

D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550

without these conditions
Therapeutics
19 Chemaly et al. Clin Infect Dis 2020 This is a randomized, double-blind, phase 2 189 patients stratified by lymphopenia The co-primary efficacy endpoints were Presatovir treatment, compared with the
The aim was to evaluate the RSV fusion trial (<200/mL) and ribavirin use were the time-weighted average change in placebo treatment, did not significantly
inhibitor presatovir in Haematopoietic cell randomly assigned to treatment (96 to the nasal RSV viral load between Days 1affect (pre-specified a ¼ 0.01) a time-
transplant recipients presatovir and 93 to the placebo) and 9 and the proportion of patients weighted average decline in the RSV viral
developing LRTCs through day 28 load from day 1 to 9 (treatment
difference, 0.33 log10 copies/mL; 95%
CI 0.64 to 0.02 log10 copies/mL; p 0.040)
or the progression to LRTC (11.2% vs. 19.5%,
respectively; OR, 0.50; 95% CI 0.22e1.18; p
0.11)
20 Aliprantis et al. Clin Pharmacol Drug Dev A phase 1 Randomized, Double-Blind, 152 healthy adults were randomized Safety, pharmacokinetics, antidrug The antibody displayed a half-life of 73
2021 Placebo-Controlled Trial 3:1 to receive a single dose of MK-1654 antibodies, and RSV serum-neutralizing e88 days and an estimated bioavailability
The aim was to Assess the Safety, or placebo in five cohorts (100 mg or antibody titres were evaluated through of 69% at the 300-mg dose. The overall
Tolerability, and Pharmacokinetics of a 300 mg as an intramuscular dose or 300 1 year safety profile of MK-1654 was similar to
Respiratory Syncytial Virus Neutralizing mg, 1000 mg, or 3000 mg as an placebo, and treatment-emergent antidrug
Monoclonal Antibody MK-1654 intravenous dose) antibodies were low (2.6%) with no
associated AEs
21 Ahmad et al. N Engl J Med 2022 This is a phase 2a, randomized, double- The participants were 18e55 years of The AUC for the RSV viral load, as The AUC for the mean total symptom score
The aim was to evaluate the safety and blind, placebo-controlled, human virus age and were assessed as being healthy measured by RT-qPCR assay of the (hours  score, with higher values
pharmacokinetic and antiviral activity of challenge trial was conducted in two parts. and serosuitable for the RSV challenge nasal-wash samples from the indicating greater severity) was 124.5 in the
multiple oral doses of EDP-938 In part 1, the trial was powered to assess (i.e. they had serum titres of pre- participants inoculated with RSV-A 600-mg once-daily group, 181.8 in the 300-
administered to healthy participants who reductions in both RSV viral load and existing RSV-A M37bespecific M37b mg twice-daily group, and 478.8 in the
were intranasally inoculated with RSV-A clinical symptoms; part 2 was planned to be antibodies of 810, which represented placebo group. In part 2, the AUC for the
Memphis 37b (M37b) initiated after completion and review of the the lowest 25th percentile of the mean total symptom score was 99.3, 89.6,
data from part 1 and was powered for RSV screened population) (n ¼ 115 part 1 and 432.2, respectively
viral load and n ¼ 65 in part 2)
Vaccines
22 Verdjik et al. Vaccines 2020 This is a first-in-human trial with primary 48 adults Safety and tolerability, nasal viral load, A single dose of 6.5 log10 CCID50 of RSVDG
The aim was to evaluate the safety of RSVDG objective to evaluate safety and shedding of and systemic and humoral immune was safe and well-tolerated in seropositive
intra nasal administration in human RSVDG (6.5 log10 CCID50) after intranasal responses were assessed at selected healthy adults. RSVDG was sufficiently
administration time points until 4 weeks after attenuated but there were no signs of
immunization induction of antibodies
23 Ruckwardt et al. Lancet Respir Med 2021 This is a randomised, open-label, phase 1 95 healthy adults between 18 and Safety and immunogenicity were No serious vaccine-associated AEs were
The aim was to evaluate the safety and clinical trial, the stabilised prefusion F 50 years were enrolled to receive DS- assessed reported. At week 44, RSV-A neutralising
immunogenicity of DS-Cav1, a prefusion F vaccine DS-Cav1 Cav1 at the 50 mg (n ¼ 30, of which activity was 3.1 fold above baseline in the
subunit vaccine n ¼ 15 with AlOH), 150 mg (n ¼ 35, of 50 mg group, 3.8 fold in the 150 mg group,
which n ¼ 15 with AlOH), or 500 mg and 4.5 fold in the 500 mg group
(n ¼ 30, of which n ¼ 15 with AlOH) (p < 0.0001). RSV-B neutralising activity
doses was 2.8 fold above baseline in the 50 mg
group, 3.4 fold in the 150 mg group, and 3.7
fold in the 500 mg group (p < 0.0001)
24 Sadoff et al. J Infect Dis 2021 This is phase 2a, double-blind, placebo- 180 adults aged 60 years Safety assessment of AEs. The immune There were no AEs leading to
This study assessed co-administration of controlled study, participants received response to influenza vaccine strains discontinuation of study vaccination and no
the investigational vaccine, Ad26.RSV.preF, Ad26.RSV.preF plus Fluarix on day 1 and was evaluated with a HI assay using deaths. Reactogenicity was generally higher
an adenovirus serotype 26 (Ad26) vector placebo on day 29, or placebo plus Fluarix turkey erythrocytes (as described after Ad26.RSV.preF vs. Fluarix, but
encoding RSV-F protein stabilized in its on day 1 and Ad26.RSV.preF on day 29 elsewhere). Vaccine-elicited RSV A2- symptoms were generally transient and
prefusion conformation (pre-F), with a (control) specific neutralizing antibodies were mild or moderate. At 28 days after the first
seasonal influenza vaccine in older adults assessed in a virus neutralization assay vaccination, the upper CIs of the HI antibody
using A549 cells (American Type geometric mean ratio (control/co-
Culture Collection CCL-185) and RSV A2 administration) for all influenza strains

D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550

virus, which expresses firefly luciferase were <2, demonstrating non-inferiority
(RSV A2 FFL)
25 Aliprantis et al. Hum Vaccin Immunother This is a randomized, partially double-blind, Healthy younger adults (ages 18 Primary objectives were safety and No serious adverse effects were reported.
2021 placebo-controlled, phase 1 dose-escalation and  49 years) and healthy older tolerability and secondary objectives Immunization with mRNA-1777 (V171)
The aim was to evaluate the safety, study adults (ages 60 and  79 years) included humoral and cell-mediated elicited a humoral immune response as
tolerability and immunogenicity of an (n ¼ 51) immunogenicity measured by increases in RSV neutralizing
investigational messenger ribonucleic acid antibody titres, serum antibody titres to
(mRNA) vaccine encoding the RSV fusion RSV prefusion F protein, D25 competing
protein (F) stabilized in the prefusion antibody titres to RSV prefusion F protein,
conformation and cell-mediated immune responses to
RSV-F peptides
26 Izikson et al. Lancet Respir Med 2022 This a phase 2 study still on-going, multi- Community-dwelling adults aged Safety assessment of AEs. 306 participants were enrolled and
The aim was to assess the safety and centre, open-label, descriptive trial at six 65 years and older, who were Haemagglutination inhibition antibody randomly assigned, of whom 296 received
immunogenicity of concomitant clinical research sites in the USA previously vaccinated with a 2-dose responses to influenza A/H1N1, A/ at least one vaccine dose. Reactogenicity
administration of high-dose quadrivalent primary schedule of the mRNA-1273 H3N2, B/Yamagata, and B/Victoria profiles were similar between the co-
influenza vaccine (QIV-HD) and a mRNA- SARS-CoV-2 vaccine (n ¼ 306) strains and SARS-CoV-2 binding administration and mRNA-1273 groups,
1273 vaccine booster dose in older adults antibody responses (SARS-CoV-2 pre- with lower re-actogenicity rates in the QIV-
spike IgG ELISA) at D1 and D22 HD group (frequency of solicited injection
site reactions) 86.0% [95% CI: 77.6e92.1],
91.3% [84.2e96.0], and 61.8% [50.9e71.9]
27 Schmoele-Thoma et al. N Engl J Med 2022 This is a phase 2a study, randomization in a Healthy adults (18 to 50 years of age) RT-qPCRconfirmed detectable RSV The vaccine efficacy was of 86.7% (95% CI:
The aim was to assess the immunogenicity 1:1 ratio, to receive a single intramuscular (n ¼ 70) infection on at least two consecutive 53.8e96.5) was observed for symptomatic
and safety of the bivalent prefusion F injection of either bivalent prefusion F days with at least one clinical symptom RSV infection confirmed by any detectable
(RSVpreF) vaccine (RSVpreF) vaccine or placebo of any grade from two categories or at viral RNA on at least two consecutive days.
least one grade 2 symptom from any The median AUC for the RSV viral load
category, the total symptom score from (hours  log10 copies per millilitre) as
day 1 to discharge, and the AUC for the measured by RT-qPCR assay was 0.0
RSV viral load in nasal-wash samples (interquartile range, 0.0 to 19.0) in the
measured by means of RT-qPCR from vaccine group and 96.7 (interquartile range,
day 2 after challenge to discharge 0.0e675.3) in the placebo group
28 Walsh et al. J Infect Dis 2022 This phase 1/2 randomized, placebo- Adults 18e49 years old (n ¼ 618) Safety end points included local No vaccine-related serious AEs occurred
The aim was evaluated safety, tolerability, controlled, observer-blind, dose-finding reactions and systemic events as through 12 months after vaccination
and immunogenicity of a novel bivalent study (NCT03529773) was conducted at 40 reported by electronic diary within
prefusion F vaccine (RSVpreF) in adults sites in the United States from April 2018 14 days after vaccination. AEs within
through November 2019 1 month after vaccination. RSV-A and
RSV-B neutralizing titres measured at
pre-specified time points through
6 months after vaccination
29 Peterson et al. J Infect Dis 2022 This is a phase 2b, multi-centre, placebo- Healthy, non-pregnant women 18‒ Safety and immunogenicity were Local reactions and systemic events were
This study evaluated concomitant controlled, observer-blind, non-inferiority 49 years of age. (n ¼ 709) assessed generally similar across vaccine groups.
(continued on next page)

1543
Table 1 (continued )

1544
Study and aim Design Sample size Outcomes/measures Results

administration of RSV stabilized prefusion F study, participants were randomized to Non-inferiority of anti-RSV-A and anti-RSV-
subunit vaccine (RSVpreF) and tetanus receive RSVpreF in a range of doses and B immune responses induced by RSVpreF
toxoid, reduced diphtheria toxoid, and formulations with Tdap or alone, or Tdap with Tdap was demonstrated compared
acellular pertussis vaccine adsorbed (Tdap) alone with RSVpreF alone. Non-inferiority of anti-
diphtheria toxoid and anti-tetanus toxoid
immune responses after administration of
RSVpreF with Tdap was demonstrated
compared with Tdap alone. Non-inferiority
was not met for anti-pertussis component
responses
30 Falsey et al. J Infect Dis 2022 This phase 1/2 study randomized Adults 18e85 years Safety and immunogenicity were Co-administration with SIIV did not appear
The aim was to assess bivalent prefusion F participants to receive placebo or 60, 120, or assessed to affect safety among younger or older
vaccine (RSVpreF) in healthy adults 240 mg RSVpreF (with or without adults. Neutralizing titres 1 and 12 months
aluminium hydroxide) alone or after vaccination were 6.9e14.9 and 2.9
concomitantly with SIIV e4.5 times, respectively, those before

D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550

vaccination. SIIV immune responses
trended lower when co-administered with
RSVpreF
31 Sadoff et al. J Infect Dis. 2022 This is a randomized, placebo-controlled, Healthy adult volunteers aged 18 The area under the VL-time curve of The median AUC for the RSV viral load
The aim was to assess the potential of double-blind phase 2a human virus e50 years with levels of RSV RSV (RSV VL-AUC) from challenge to (hours  log10 copies per millilitre) as
Ad26.RSV.preF to protect against RSV challenge trial neutralizing antibodies compatible discharge determined by quantitative measured by RT-qPCR assay was 0.0
infection and disease in an RSV human with susceptibility to RSV infection RT-PCR assay of nasal-wash samples (interquartile range, 0.0e19.0) in the
challenge model from the participants inoculated with vaccine group and 96.7 (interquartile range,
RSV-A M37b 0.0e675.3) in the placebo group. The
geometric mean factor increase from
baseline in RSV-Aeneutralizing titres
28 days after injection was 20.5 (95% CI:
16.6e25.3) in the vaccine group and 1.1
(95% CI: 0.9e1.3) in the placebo group
Falsey et al. N Engl J Med 2023 This is a randomized, double-blind, Adults who were 65 years of age or The primary end point was the first Vaccine efficacy was 80.0% (94.2% CI: 52.2
The aim was to assess the first occurrence of placebo-controlled, phase 2b, proof-of- older were randomly assigned in a 1:1 occurrence of RSV-mediated lower e92.9), 75.0% (94.2% CI: 50.1e88.5), and
RSV-mediated lower respiratory tract concept trial to evaluate the efficacy, ratio to receive vaccine or placebo respiratory tract disease that met one of 69.8% (94.2% CI: 43.7e84.7) for case
disease after vaccination Ad26.RSV.preF immunogenicity, and safety of an (n ¼ 5782) three case definitions: 3 or more definitions 1, 2, and 3, respectively
eRSV pre-F protein vaccine in older adults Ad26.RSV.preFeRSV pre-F protein vaccine symptoms of LRTI (definition 1), 2 or
more symptoms of LRTI (definition 2),
and either two or more symptoms of
LRTI or one or more symptoms of LRTI
plus at least one systemic symptom
(definition 3)
Papi et al. N Engl J Med 2023 This a placebo-controlled, phase 3 trial to Adults 60 years of age or older to were The criterion for meeting the primary Vaccine efficacy was 94.1% (95% CI, 62.4
The aim was to show vaccine efficacy of one evaluate the vaccine efficacy of RSVPreF3 randomized to receive a single dose of objective was a lower limit of the CI e99.9) against severe RSV-related lower
dose of the RSVPreF3 OA vaccine against OA an AS01E-adjuvanted RSV prefusion F around the efficacy estimate of more respiratory tract disease (assessed on the
RSV-related lower respiratory tract disease, protein-based candidate vaccine than 20% basis of clinical signs or by the investigator)
confirmed by RT-PCR, during one RSV (RSVPreF3 OA) or placebo before the and 71.7% (95% CI, 56.2e82.3) against RSV-
season RSV season (n ¼ 24 966) related acute respiratory infection. Vaccine
efficacy was similar against the RSV-A and B
subtypes (for RSV-related lower respiratory
tract disease: 84.6% and 80.9%, respectively;
for RSV-related acute respiratory infection:
71.9% and 70.6%, respectively)

AE, adverse event; aOR, adjusted odds ratio; AUC, area under the curve; CRP, common respiratory pathogen; HI, hemagglutination inhibition; HR, Hazard Ratio; ICU, intensive care unit, ILI, influenza-like illness; IMV, invasive
mechanical ventilation; KPSC, Kaiser Permanente Southern California; LRTC, lower respiratory tract complication; LRTI, lower respiratory tract infection; NIV, non-invasive ventilation; NPI, non-pharmaceutical interventions;
NPS, nasopharyngeal swab; RSV, respiratory syncytial virus; SIIV, seasonal inactivated influenza vaccine.
 D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550 1545

the emergency room, and 16% required hospitalization. Two high- Other immunocompromised subgroups are also more likely to
risk patients with RSV infection (4%) died [8]. A more recent sys- develop more severe RSV infections [29].
tematic review and meta-analysis, including 16 observational Recent studies focusing on immunocompromised adults remain
studies and 762 084 older participants, showed that the incidences scarce. A recent United States study reported that immunosup-
of hospitalization and mortality were similar for RSV and influenza pressed patients bear the greatest burden of RSV hospitalizations
[26]. In another study carried out in California, patients infected (1288e1562/100 000 immunosuppressed individuals), respec-
with RSV were more prone to have congestive heart failure (35.3% tively, 5 and 1.5 times higher than immunocompetent adults aged
vs. 24.5%, p < 0.001) and chronic obstructive pulmonary disease 18e64 and immunocompetent adults aged 65þ [34]. ICU admis-
(COPD; 29.8% vs. 24.3%, p 0.006) as underlying conditions. The sions were also frequent (underlying lung disease, 28% of patients;
presence of RSV infection was linked to higher chances of having a immunocompromised, 36%; older adults 65 years, 26%; and other
hospital stay lasting 7 days (OR ¼ 1.5; 95% CI: 1.2e1.8, p < 0.001) adults, 23%). The overall median hospital length of stay was similar
and a diagnosis of pneumonia (OR ¼ 2.7; 95% CI: 2.2e3.2, p < 0.001) between groups [35]. In a French study, 30% of 1168 hospitalized
[27]. Another study also reported that pneumonia was more com- RSV cases were immunocompromised, mainly patients with solid
mon in RSV patients: 21.2% (24/113) vs. 9.1% (48/526, p 0.001, me- cancer or haematological malignancies [14].
dian age at 74 years old) [28]. Finally, a Chinese study including 51
adults hospitalized with an RSV infection (median age of 64.1 years) RSV prevention and treatment candidates in development
reported that cardiovascular complications during hospitalization
were more frequent in the RSV group than in the influenza A group: Vaccines
51.0% vs. 34.4%, p 0.024 (chi-square test), as was pneumonia: 58.8%
vs. 38.4%, p 0.006 (chi-square test) [29]. A recent meta-analysis RSV vaccine candidates for paediatric, maternal, or older pop-
estimated that, by 2025, the number of RSV acute respiratory ulations use four approaches: recombinant vector, protein-based
infection cases, hospitalizations, and in-hospital deaths in high- (inactivated, subunit, or particle-based), live attenuated, and
income countries could reach 5.7 million (95% CI: 3.0 mil- nucleic acid vaccines [36]. Herein, we only report the results of
lione10.9 million), 510 000 (95% CI: 330 000e790 000), and 37 000 phase 3 trials of vaccines evaluated in older adults.
(95% CI: 18 000e74 000), respectively [30] (Table 1). Two subunit vaccines using the RSV pre-F protein have re-
ported phase 3 trial results. One is a bivalent vaccine comprising
subtype A and B of RSV pre-F proteins (60 mg each) (RSVpreF). This
Patients with comorbidities
vaccine showed 86.7% (95% CI: 53.8e96.5) efficacy in a human
challenge study with RSV-A in younger adults [37]. In the phase 3
This includes patients with an underlying chronic disease,
RENOIR trial that evaluated this vaccine in an older population, the
including heart failure, lung disease, diabetes, or renal failure. In
preliminary results showed a vaccine efficacy to prevent RSV-
New York and Rochester (United States), between 2017 and 2020, a
associated lower respiratory tract illness with at least two or
prospective study was conducted with population-based surveil-
three signs or symptoms was of 66.7% (96.66% CI: 28.8e85.8) and
lance to estimate the incidence of RSV hospitalization among adults
85.7% (96.66% CI: 32.0e98.7), respectively [38]. In addition, Walsh
and those with specific comorbidities [31]. The incidence rates
et al. [39] reported that no vaccine-related serious adverse events
among patients with COPD, coronary artery disease (CAD), and
occurred in older patients through 12 months after vaccination.
congestive heart failure were notably elevated, ranging from 3 to 13
The second vaccine is monovalent and comprises Rsvpref protein,
times, 4 to 7 times, and 4 to 33 times, respectively, in comparison
adjuvanted with AS01, a liposome-based adjuvant (RSVPreF3 OA).
with patients without these conditions. Specifically, adults dealing
The AReSVi-006 phase 3 trial preliminary results indicated a vac-
with COPD exhibited hospitalization rates 3.2e13.4 times higher
cine efficacy of 94.1% (95% CI: 62.4e99.9) against severe RSV-
than those without COPD, whereas adults with asthma faced esti-
related lower respiratory tract disease [40]. The safety profile of
mated hospitalization rates 2.0e3.6 times greater than individuals
this vaccine in the older population was also satisfactory. These
without asthma. Similarly, adults diagnosed with diabetes pre-
phase 3 trials remain on-going to assess the duration of protection
sented hospitalization rates 2.4e11.4 times higher than those
but based on the interim results both vaccines have been approved
without diabetes. Lastly, adults with CAD were estimated to have
in Spring 2023 (by U.S. Food and Drug Administration (FDA) and
RSV-related hospitalization rates 3.7e7.0 times higher than in-
European Medicines Agency (EMA) for RSVPreF3 OA [Arexvy
dividuals without CAD. A recent study by Shi et al. estimated the
(GSK)] and by FDA for RSVPreF [Abrysvo (Pfizer)]) for active im-
incidence, hospitalization rate, and in-hospital case fatality ratio
munization of individuals 60 years of age and older for the pre-
(hCFR) of RSV-ARTI in adults with comorbidities based on a sys-
vention of lower respiratory tract disease caused by RSV [41,42]. In
tematic review of studies published between January 1996 and
the spring of 2023, the FDA had granted approval to RSVPreF
March 2020. The annual incidence rate of RSV-ARTI among adults
(Abrysvo [Pfizer]) for its use in pregnant women. This approval is
with any underlying medical condition was calculated at 37.6 per
aimed at preventing infections in new-borns. The decision was
1000 individuals per year (95% CI: 20.1e70.3), whereas the seasonal
made after assessing the safety and effectiveness of the vaccine in
incidence rate stood at 28.4 per 1000 individuals per season (95%
combating severe cases of RSV-associated lower respiratory tract
CI: 11.4e70.9). In addition, the hCFR in high-income countries was
illness in infants. The evaluation was conducted through a phase 3
recorded at 11.7% (95% CI: 5.8e23.4%) [32]. No data were available
randomized controlled trial involving pregnant women in their
for low- and middle-income countries.
24the36th weeks of gestation [43]. The vaccine demonstrated
efficacy against severe RSV-associated lower respiratory tract
Immunocompromised patients illness in infants within 90 and 180 days after birth, and no safety
concerns were observed.
Lung and haematopoietic stem cell transplant (HSCT) recipients Recombinant vector vaccines use a modified and defective vi-
are known to have the highest RSV-related burden with both short- rus to induce humoral and cellular immunity. Two vaccines are
term complications, such as hospitalization, ICU admission, and currently registered in phase 3, Ad26.RSV.PreF and MVA-BN-RSV.
death for LRTI, and long-term complications, such as bronchiolitis The first is a vaccine comprising an association of a recombinant,
obliterans syndrome/chronic lung allograft dysfunction [33]. replication-incompetent adenovirus serotype 26 vector encoding
1546 D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550

a conformation-stabilized Rsvpref protein (Ad26.RSV.preF) with a Ribavirin

recombinant Rsvpref protein with no adjuvant. In a randomized,
double-blind, placebo-controlled, phase 2b trial, the vaccine effi- Both oral and aerosolized ribavirin are authorized for treating
cacy of Ad26.RSVpre-F ranged between 80.0% (94.2% CI: RSV, supported by evidence showcasing a decrease in the
52.2e92.9) and 69.8% (94.2% CI: 43.7e84.7) according to case requirement for additional oxygen. However, the utilization of
definitions. After vaccination, RSV A2 neutralizing antibody titres ribavirin is restricted due to concerns regarding its effectiveness,
increased 12-fold between baseline and day 15. The frequency of safety, and financial implications. At present, the pre-dominant
serious adverse events was similar in the vaccine and placebo approach to RSV treatment revolves around providing supportive
groups (4.6% and 4.7%, respectively) [44]. Despite these encour- care [7]. Ribavirin has not significantly impacted clinically relevant
aging results, the pharmaceutical company announced on March outcomes among immunocompromised and older adults, such as
29, 2023, that they would stop the development of their RSV mortality, length of hospital stay, mechanical ventilation, or ICU
vaccine for adults. The second recombinant vector vaccine, MVA- admission [57,58].
BN-RSV, is a poxvirus-vectored vaccine encoding internal (M and In adult, haematopoietic cell transplant recipients with RSV
N) and external (F, G[A] and G[B]) RSV proteins. In the phase 2a infection, early use of nebulized ribavirin was associated with
randomized, double-blind, placebo-controlled human challenge reduced morbidity and mortality [59]. Oral ribavirin might be an
trial, 63 healthy participants aged 18e50 received MVA-BN-RSV or alternative to nebulized ribavirin in this population. Indeed, a study
placebo and were then challenged 4 weeks later with RSV-A reviewing 124 haematopoietic stem cell transplant recipients with
Memphis 37b. MVA-BN-RSV vaccination resulted in lower viral RSV infections found that the progression rate to LRTI and 30-day
load and symptom scores and a 79.2% efficacy in symptomatic mortality were similar in patients treated with oral (n ¼ 54) and
laboratory-confirmed infection in 12 days after the challenge. It nebulized (n ¼ 70) ribavirin. The progression rate to LRTI was
induced broad immunogenicity with humoral (serum immuno- approximately 27%, and the 30-day mortality rate was roughly 10%
globulin A and G) and cellular responses (interferon-g-producing in both treatment groups.
cells) at 2 and 6 months after vaccination. The on-going VANIR In a recent meta-analysis, the primary objective was to consoli-
phase 3 trial evaluates this vaccine's efficacy in patients aged 60 date the available evidence regarding the effectiveness and safety of
and older [45]. ribavirin in treating LRTI associated with RSV in immunocompro-
The mRNA-1345, encoding for the stabilized RSV pre-F, uses the mised patients, specifically those with haematological malignancies
same lipid nanoparticle formulation as the SARS-CoV-2 vaccine and those who have undergone lung transplants. The analysis
SpikeVax [46]. It is the only nucleic acid vaccine in phase 3. Pre- indicated that there were no significant differences in terms of
liminary results of phase 3, randomized, observer-blind, placebo- mortality when comparing aerosolized or oral ribavirin to standard
controlled trial, have been reported at European Congress of Clinical care (risk ratio [RR]: 0.63; 95% CI: 0.28e1.42). However, when
Microbiology & Infectious Diseases (ECCMID) 2023, showing an examining subgroups, it was noted that mortality rates were notably
83.7% (95.88% CI: 66.0e92.2) efficacy in preventing confirmed RSV lower in individuals with haematological conditions (RR: 0.32; 95%
LRTI with at least two lower respiratory symptoms with no safety CI: 0.14e0.71), whereas there was no substantial difference
concerns [47]. observed among recipients of lung transplants (RR: 0.89; 95% CI:
Notably, several phase 1 studies are currently on-going, aiming 0.31e2.56) [60]. This limited efficacy of ribavirin was also shown in
to assess the safety and reactogenicity of combined mRNA vaccines another recent meta-analysis showing that ribavirin use was not
(mRNA-1045 [influenza and RSV] and mRNA-1230 [influenza, RSV, associated with lower mortality (pORs 0.81; 95% CI: 0.40e1.66) [61].
and SARS-CoV-2]) compared with mRNA-1010 (influenza), mRNA- Some studies also evaluated the use of combination therapy,
1345 (RSV), and mRNA-1273.214 (SARS-CoV-2) vaccines in mainly in HSCT recipients. A review of HSCT recipients found that
healthy older adults [48]. patients treated with ribavirin and an immunomodulator had better
Finally, to our knowledge, no live attenuated vaccine is currently outcomes regarding LRTI progression and mortality rates than those
in phase 3. treated with ribavirin alone. However, most studies included in the
review had severe methodological limitations [62]. Overall, combi-
Monoclonal antibodies nation therapy associating ribavirin with immunomodulators, such as
Intravenous Immunoglobulin (IVIG), RSVeIVIG, or palivizumab, has
Palivizumab is no longer the only licensed monoclonal antibody shown variable success, and the optimal treatment is uncertain [63].
(mAb) to prevent serious LRTI caused by RSV in children at high risk
of RSV disease. Indeed, nirsevimab, a new half-life-extended mAb, Fusion inhibitors
has recently been approved by the FDA and EMA based on the ef-
ficacy results on medically attended RSV-associated LRTI of two Fusion inhibitors are another class of drugs being tested for RSV
randomized placebo-controlled trials in healthy preterm infants treatment.
(phase 2b) and healthy late preterm and term infants (Phase III In a phase 2 clinical trial in healthy adult volunteers challenged
MELODY trial) [49,50], and on the results of one randomized with RSV, different doses of the fusion inhibitor JNJ-53718678
palivizumab-controlled trial that assessed its safety and pharma- (rilematovir) significantly reduced viral load and clinical disease
cokinetics in at-risk preterm infants (Phase II/III trial) [51,52]. severity [64]. In a double-blind, phase 2a trial, RSV-positive adult
Clesrovimab, another long-acting mAb, is currently in phase 3 outpatients (n ¼ 72) were randomly assigned to receive rilematovir
development [53,54]. Nirsevimab and clesrovimab target epitopes 500 mg, 80 mg, or placebo once daily for 7 days. Individuals
located on the RSV-F protein, either in its prefusion conformation receiving rilematovir presented reductions in RSV RNA viral loads
(nirsevimab and clesrovimab) or in its post-fusion conformation and faster time to viral clearance compared with placebo-treated
(clesrovimab). Both clesrovimab and nirsevimab safety are patients. Additionally, key RSV symptom resolution was acceler-
currently evaluated in early phases among adults [55,56]. Efficacy ated with rilematovir, supporting its potential as an early treatment
and safety need to be assessed in at-risk adults, particularly in in RSV-infected adults [65]. However, adults at risk only accounted
immunocompromised patients. Their potential use in this popula- for 36% of the 72 patients included, and the results for them showed
tion seems attractive to reduce health expenses due to hospital no efficacy, which is difficult to interpret due to the small sample
visits, complementary examinations. size.
 D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550 1547

Presatovir showed a good safety profile and efficacy in reducing received steroids in a recent study [82]. Larger studies should be
viral load and clinical symptoms in a phase 2 human challenge [66]. conducted on this topic, especially given the large use of gluco-
Presatovir is, to date, the only fusion inhibitor that has been corticoids in RSV-infected patients and the benefits observed dur-
assessed in an immunocompromised population. Three different ing the COVID-19 pandemic.
phase 2 randomized, double-blind trials in haematopoietic cell
transplant recipients with upper respiratory tract infections [67], Discussion
haematopoietic cell transplant recipients with LRTI [68] and lung
transplant recipients [69] found no efficacy based on clinical and Today, RSV is recognized as a threat to infants and older adults,
virological criteria after a median time of administration of 6, 4, and especially those with underlying chronic diseases. However, its
6 days after symptoms onset, respectively. Post hoc analysis sug- impact on at-risk adults is still under-recognized due to the lack of
gested an antiviral effect on the reduction of LRTI among patients awareness among healthcare professionals and the general popu-
with lymphopaenia and in those treated earlier in the trial with lation, the lack of systematic use of virological diagnostics and a
haematopoietic cell transplant recipients with upper respiratory robust data collection and surveillance systems, and the absence of
tract infections [67]. RSV-targeted treatments [41,42]. The rapidly evolving landscape of
Sisunatovir showed a good safety profile and efficacy in RSV preventive treatments should be an opportunity to set precise
reducing viral load and clinical symptoms in a phase 2 human and formalized prevention strategies, including improving aware-
challenge [70]. ness. Indeed, in the past few months, two RSV vaccines for older
Other fusion inhibitors with activity against RSV in preclinical adults and one long-acting monoclonal antibody for infant pro-
studies have been tested, alone or in combination, such as ziresovir tection have been approved and might be available in Fall 2023.
(AK0529) or BMS43377 [71]. Vaccination strategies will need to be evaluated and discussed
based on interim and final safety and efficacy results, including
Nucleoprotein inhibitors duration of protection. This will guide decisions on RSV vaccination,
notably if these vaccines should be seasonal, as is currently the case
EDP-938 acts by modulating the viral nucleoprotein and having a with influenza and SARS-CoV-2, and if these vaccines' co-
potential high barrier to resistance [72]. In a phase 2a human chal- administration is safe and efficient. It also raises the issue of vac-
lenge double-blind trial evaluating the efficacy of EDP-938, EDP-938 cine availability worldwide and highlights the importance of
showed superiority over placebo, significantly reducing viral load, working with health policymakers to advocate for and implement
symptom scores, and mucus production. The study did not report broad vaccination strategies. We can only hope that the use of
any safety concerns across various dosing regimens [73]. Two phase nirsevimab in infants will have a tremendous impact on the RSV
2b, randomized, placebo-controlled studies are on-going in hae- burden in this age group. Based on the COVID-19 experience, this
matopoietic cell transplants adult recipients [74] and in non- long-acting monoclonal antibody and future others must be
hospitalized adults at high risk of severe form of RSV disease [75]. assessed in the adult population, especially in the most at-risk
EP-023938 is another nucleoprotein inhibitor of RSV, targeting patients, such as immunocompromised patients, in whom vaccine
the virus replication machinery of both RSV-A and RSV-B, with a efficacy is expected to be lower and shorter. In this population, their
phase 2 trial currently on-going [76]. use as a curative treatment for patients with severe disease should
be evaluated as well. RSV-targeted treatments are also in the
Polymerase inhibitors pipeline and are expected in the coming years to reinforce thera-
peutic options. Some oral and inhaled antivirals showed promising
PC786 is a nebulized non-nucleoside inhibitor of RSV polymerase. results in human challenge trials, but this translated to limited ef-
It showed a faster reduction of RSV viral load and clinical symptoms ficacy in phase 2 trials in at-risk patients. This might be explained
in a phase 2 randomized, placebo-controlled human challenge [77]. A by the differences in patients' immune profiles and/or underlying
phase 2 randomized, placebo-controlled trial in haematopoietic diseases, and by the timing of administration which is critical in
transplant adult recipients has been interrupted [78]. acute respiratory diseases as it is already known with influenza and
ALS-8176 (lumicitabine) is another non-nucleoside inhibitor. In SARS-CoV-2.
a phase 2 clinical trial randomized 62 adults with RSV infection to The forthcoming approval of vaccines and monoclonal anti-
receive ALS-8176 or a placebo, the results show that ALS-8176 was bodies reinforces the need for efficient virological and clinical
associated with a significant reduction in viral load compared with surveillance of RSV infections, notably to assess viral circulation
the placebo [79]. Its development has been stopped due to dose- and evolution and its impact on the efficacy of vaccines and
related neutropenia and the absence of efficacy in treated infants. monoclonal antibodies, as it has been implemented for SARS-CoV-2
and influenza.
Glucocorticoids Improved diagnostic strategies should also be discussed. Indeed,
diagnosing RSV infections efficiently and rapidly is crucial to be able
Glucocorticoid therapy for RSV-related respiratory diseases re- to prevent severe diseases. A foundation for addressing the burden of
mains controversial [80]. In a study published in 2011, 33 of 50 respiratory virus infections is conducting syndromic testing,
(66%) patients hospitalized for RSV infection with various degrees including SARS-CoV-2, influenza, RSV, and other respiratory viruses
of severity, from bronchitis to respiratory failure, received systemic such as metapneumoviruses and rhinoviruses, which are also
steroids for a mean duration of 11 days. Those who received ste- responsible for severe pneumonia [83]. However, the cost of these
roids wheezed more frequently (wheezing duration 12.2 ± 6.1 days assays hinders the design of practical and efficient testing
vs. 8.2 ± 4.8 days) and were less often febrile (temperature algorithms.
36.9 C ± 0.9 C vs. 37.7 C ± 1 C). No serious adverse events related The coming years promise to be extremely exciting in the RSV
to steroids, no significant differences in peak viral load (3.63 log prevention landscape. The best use of the new prevention, diag-
10 þ 1 vs. 3.5 log 10 þ 1), and no significant differences in duration nostic, and therapeutic tools must be defined. The viral evolution
of RSV shedding (12.67 days vs. 14.13 days) were found [81]. and resistance must also be studied to guide new monoclonal an-
Although no significant evidence exists of a positive effect of glu- tibodies, antivirals and vaccine elaboration in child and adult
cocorticoids in RSV-related infection, 78.1% of older patients populations.
1548 D. Bouzid et al. / Clinical Microbiology and Infection 29 (2023) 1538e1550

Author contributions respiratory syncytial virus infection in France, 2017e2019: an observational

study. Eur Respir J 2022;59:2100651. https://doi.org/10.1183/13993003.
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script. BV, NP-S, QLH, and VMF were responsible for the wri- Characteristics and outcomes of patients in the ICU with respiratory syncytial
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Transparency declaration
hospitalized older adults. Influenza Other Respir Virus. 2022;16:1151e60.
https://doi.org/10.1111/irv.13043.
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sentations. PL has received payment or honoraria for lectures, pre- COVID-19 pandemic d United States, 2020e2021. MMWR Morb Mortal Wkly
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