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Respiratory Syncytial Virus: Navigating Prevention Strategies for Older and At-Risk Adults
INTRODUCTION
RESPIRATORY SYNCYTIAL VIRUS (RSV) is a pneumovirus frequently associated with respiratory illnesses.1-3 While RSV has been known to cause serious complications in infants and young children, it has also been associated with substantial clinical and economic impacts in adults who are older, reside in nursing homes or long-term care facilities, or have certain medical conditions including chronic heart or lung disease.4-7 Progress has been made towards RSV prevention with the approval of 3 new RSV vaccines,8-10 but continued efforts are needed to ensure routine accessibility of these vaccines to the most vulnerable populations. With a focus upon older adults and adults with comorbidities, this article will review the clinical and economic impact of RSV, guidance from the CDC, preventive strategies, and managed care considerations surrounding vaccination.
OVERVIEW
Although RSV is a frequent cause of acute respiratory infections (ARIs), an estimation of its incidence has proven challenging due to a lack of routine testing, overlapping clinical presentations with other syndromes, and low public awareness of RSV.3,7,11,12
In 2005, RSV accounted for approximately 177,000 hospitalizations and 14,000 deaths annually in individuals 65 years or older, highlighting the burden of RSV on the health care system.12
Transmission
RSV may be transmitted via direct physical contact with the virus (eg, via kissing), exposure to respiratory droplets when infected individuals cough or sneeze, or contact with contaminated surface followed by contact with mucous membranes. RSV shares similarities with other respiratory viruses (Table 1), although there can be slight differences in symptom onset and windows of contagion.13-15
The infectious period can begin 1 to 2 days before symptom onset and may last for approximately 3 to 8 days in hosts who are not immunocompromised.14 Most children will be exposed to RSV prior to their second birthday, and repeated infections throughout life are common.1,14 Within families, older siblings or parents have been frequent sources of RSV infections in infants.16
Symptoms and Complications of RSV
Due to significant overlaps in signs and symptoms, RSV infection can be difficult to differentiate from other respiratory viruses.11 In infants, RSV symptoms may include rhinorrhea, decreases in feeding, increases in irritability, and apnea.17 In most adults, RSV symptoms mimic those of a minor cold and include cough, headache, wheezing, and sore throat.5,18 Symptoms such as fever and fatigue may be present but at a lower frequency (26%-50%) than typically seen with influenza (51%-75%).11 Most adult patients will typically have mild infections lasting less than 5 days; however, in high-risk populations, RSV can lead to serious complications including lower respiratory tract disease (LRTD) (eg, pneumonia), exacerbations of congestive heart failure (CHF), worsening of asthma or chronic obstructive pulmonary disease (COPD), and acute respiratory failure leading to death.4,5,11
Epidemiology
Like other respiratory viruses, RSV seasonality can vary by region, and peak circulation typically occurs during the winter in temperate climates.2,19 In the United States, RSV seasonality begins in the fall, peaks in the winter, and begins to wane in the spring.20 In most areas of the world, the time frame of RSV seasonality remains relatively consistent with only minor variations of approximately 1 to 3 weeks from year to year.2 Interestingly, during the 2020-2022 respiratory seasons that occurred along with the COVID-19 pandemic, trends in RSV seasonality were heavily disrupted. Based on preliminary data from the National Respiratory and Enteric Virus Surveillance System, it appears that RSV seasonality now has returned to a more predictable state.19
Risk Factors for Severe Disease
Patients at high risk for severe RSV infection include those of advanced age—especially 75 years or older—and those with chronic cardiopulmonary comorbidities including lung disease (COPD, asthma), cardiovascular disease (CHF, coronary artery disease [CAD]), diabetes mellitus, and weakened immune status.5 In a large prospective study conducted in 2 regions in New York across 3 RSV seasons from 2017 to 2020 that involved 1099 hospitalized patients with RSV infection, hospitalization rates for RSV illness were highest for adults at least 65 years of age (136.9-255.6/100,000 population) when compared to those aged 50 to 59 years (33.5-57.5/100,000 population) and others aged 18 to 49 years (7.7-11.9/100,000 population). Additionally, the incidence of hospitalization was higher among adults with COPD (incidence rate ratio [IRR], 3.2-13.4), asthma (IRR, 2-3.6), diabetes (IRR, 2.4-11.4), CHF (IRR, 4-33.2), and CAD (IRR, 3.7-7.0) compared with adults without these comorbid conditions.7 Identification of patients at highest risk for severe RSV disease is critically important when evaluating RSV prevention strategies such as vaccination.
CLINICAL IMPACT
The impact of RSV infection on clinical outcomes is not benign— rates of hospitalization and death are comparable to those of influenza.12,21
In older adults, the clinical impact may be even greater.3 Results of a study evaluating over 1500 adults with respiratory infections caused by RSV, SARS-CoV-2, or influenza A/B reported that older patients (average age, 75.1 years) with RSV-related illness had more severe outcomes than did those with influenza A/B.3 Odds of mechanical ventilation and admission to an intensive-care unit (ICU) were higher in the RSV group than in the influenza-B group (odds ratio [OR] for mechanical ventilation: 2.33 [P < .001]; OR for ICU admission: 1.98 [P = .018]). On average, patients with RSV infections also had a longer hospital length of stay than did those with influenza-B infection (12.66 vs 8.76 days; P < .001).3
Additional clinical considerations include the high percentage of patients admitted with RSV who receive inappropriate antibiotic courses. In a study by Belongia and colleagues, 77% of patients with RSV infection received a new antibiotic prescription.22 Widespread overuse of antibiotics likely to be ineffective contributes to global antimicrobial resistance and increases the risk for poor patient outcomes.23
Mortality related to RSV infection can vary, with patients of older age experiencing some of the highest mortality rates compared to those of other age groups.24,25
In a study by Tseng and colleagues, mortality associated with RSV infections in patients aged at least 60 years was evaluated at various time points. Of 664 patients hospitalized with RSV illness, all-cause mortality at 1, 3, 6, and 12 months was 8.6%, 12.3%, 17.2%, and 25.8%, respectively. Patients with advanced age, pneumonia, or CHF had significantly poorer chances of survival during the year following admission than did patients with other or no comorbidities (P < .001 for all), highlighting the long-term clinical sequelae that RSV infections can cause.26
Additional clinical impacts of RSV infection can be seen when evaluating patient functionality during daily activities and following hospital discharge.27,28 In a study conducted by Branche and colleagues, longitudinal changes in functionality were evaluated in 302 patients 60 years or older who were admitted with RSV infection. With use of the Lawton-Brody Instrumental Activities of Daily Living scale, 31.8% of patients sustained decreased functionality compared to baseline at 6 months after discharge.28 Additionally, in a study evaluating RSV infection among people experiencing homelessness, approximately 39% of patients reported a substantial decline in their ability to perform regular activities in the setting of RSV infection.27 Not only can this decline impact patient satisfaction and quality of life, but it can also have economic impacts for the patient and the health care system.
ECONOMIC IMPACT
The economic impact of RSV infection can be considerable, particularly for older adults. The breakdown of direct versus indirect costs can vary depending on patient age; when both are considered, however, the expenditures are large.6,29-31
Direct Costs
In a study published by Mesa-Frias and colleagues, 2 de-identified insurance claims databases were evaluated to assess direct health care costs among individuals with RSV infection in the US as coded according to the International Statistical Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM); and the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). The authors evaluated all-cause weekly health care costs starting 8 weeks prior to the index date of RSV infection and for up to 4 weeks after. The overall incidence of RSV infection ranged from 22 per 100,000 people to 52.9 per 100,000 people (Optum) and 23.4 per 100,000 people to 63.6 per 100,000 people (MarketScan). When evaluating the economic burden of RSV, an increase in costs was noted the week before index RSV infection (Optum, $2325; MarketScan, $2080) and the week after (Optum, $9523; MarketScan $551) compared with 2 to 8 weeks before RSV infection in all populations.6
When compared to the overall adult RSV population with use of the MarketScan database, weekly costs were higher in patients 60 years and older and aged 18 to 59 years who were at high risk of severe RSV infection. These results highlighted the financial burden of RSV in adults at least 60 years of age. However, important limitations included the reliance on ICD-coded diagnosis, inclusion only of adults seeking medical care for severe cases, and a possible underestimation of costs if payment amounts were capitated.6
Similarly, Carrico and colleagues sought to evaluate the economic burden of RSV infection in adults 60 years or older, those aged 50 to 59 years, and individuals aged 18 to 49 years with risk factors for RSV infection using a cost-of-illness model. An annual estimated economic burden of $6.6 billion (2021 US$) was projected in adults at least 60 years of age, with 44% representing direct hospital costs. In patients aged 50 to 59 years, a substantial $1.1 billion estimated annual economic burden was projected, with a larger percentage dedicated to indirect costs of RSV morbidity and mortality. In patients aged 18 to 49 years with risk factors, the estimated annual cost was highest among patients with obesity, diabetes, or asthma. Only 4% of all RSV infections were predicted to result in hospitalization, but these cases were projected to account for 94% of direct hospital costs at an estimated $2.7 billion. The study had limitations including the reliance on Medicare data and the use of a single study for case severity data; however, the results highlight the importance of interventions designed to mitigate severe RSV infections, which can lead to high health care expenditures.29
Indirect Costs
Morbidity and mortality related to RSV infection can be associated with high indirect costs that have traditionally been characterized from a market productivity loss perspective in the setting of wages lost.31-33 Importantly, indirect costs should also represent non-market productivity losses that include caregiving, household activities, and volunteering that may more significantly impact older adults. In the study by Carrico and colleagues, indirect costs were higher among adults aged 60 to 64 years when compared with those for adults 65 years or older. Additionally, among patients in younger age groups (50-59 years), 61% of costs were indirect as compared with approximately 51% in adults 65 years or older. When evaluating adults aged 18 to 49 years with high-risk comorbidities, indirect costs were responsible for approximately 72% of the projected annual economic burden.29 Similar findings were seen in a study by Verelst and colleagues in which both market and non-market indirect costs were estimated in adults 60 years or older with RSV infection using estimated time losses described in the literature based on inpatient, outpatient, or nonmedically attended cases. Using a Markov model, the authors estimated an annual $4.7 billion in productivity losses among older adults, with per capita RSV-related productivity losses declining as age increased (2022 US$).30,31 These findings highlight the importance of taking a more holistic approach when evaluating the true economic burden of RSV infection.
CDC GUIDANCE
There are currently no FDA-approved treatment modalities for RSV in adults; its management largely is focused on supportive care alongside increased efforts for RSV prevention. As of July 2024, 3 vaccines for prevention of RSV-associated LRTD have been approved by the FDA (Table 2).8,10,34-38 Beginning in June 2024, the CDC recommends a single dose of RSV vaccine for adults 75 years or older and adults 60 to 74 years who are at increased risk of severe RSV infection or who live in nursing homes. Because the vaccine is not currently an annual vaccine, the recommendation applies to individuals who were not vaccinated against RSV in 2023.39,40
The CDC recognizes the previously described chronic underlying medical conditions (eg, lung disease, cardiovascular disease) as risk factors for severe RSV disease.39 Adults 60 years or older who are frail, residing in long-term care facilities, or with compromised immunity are also at increased risk.40 The RSV vaccine can be administered at any time in eligible populations, although administration before RSV season is ideal.39
The 2024 recommendation replaces the CDC’s 2023 recommendation, which was based on shared decision-making between patient and provider, and simplifies decision-making for clinicians, patients, and other stakeholders. The updated recommendation is founded upon disease burden, RSV effectiveness, and cost-effectiveness studies that include real-world data gathered since the first vaccine was approved in 2023. The CDC advises that health care providers recommend RSV vaccination to eligible patients.39
In their June deliberation, the Work Group for the CDC’s Advisory Committee on Immunization Practices agreed that RSV-associated disease is or probably is a public health problem for adults aged 50 to 59 years at increased risk of severe RSV disease. However, the group sought at least 1 complete season of safety surveillance data before deciding upon a vaccination recommendation for this population.41
RSV PREVENTION
Prevention of RSV-LRTD is a critical step in mitigating poor clinical outcomes and increased health care expenditures. Two of the RSV vaccines currently approved for patients at least 60 years of age are recombinant stabilized prefusion F (PreF) protein vaccines including adjuvanted RSVPreF3 OA (Arexvy; GSK) and bivalent RSVpreF (Abrysvo; Pfizer).8,9 RSVPreF3 OA is also approved for adults aged 50 to 59 years who are at increased risk of RSV-LRTD.9 On May 31, 2024, an mRNA-based PreF vaccine from Moderna, mRNA-1345 (mRESVIA), also received FDA approval for use in patients 60 years and older.10,34,42
RSVPreF3 OA (Arexvy; GSK)
On May 3, 2023, RSVPreF3 OA became the first RSV vaccine to be granted FDA approval. This was based on the results of an ongoing, international, placebo-controlled phase 3 trial (NCT04886596) taking place in 17 countries and occurring over at least 2 (Southern Hemisphere) to 3 (Northern Hemisphere) consecutive RSV seasons.35,43 Adults 60 years or older were recruited from May 2021 through January 2022 and randomly assigned to receive 1 dose of the RSVPreF3 OA vaccine (n=12,467) or placebo (n=12,499). After 1 Northern Hemisphere RSV season and a median follow-up of 6.7 months, vaccine efficacy against RSV-related LRTD was 82.6% (95% CI, 57.9%-94.1%), with efficacy against severe RSV-related LRTD being even greater at 94.1% (95% CI, 62.4%-99.9%).35 After 2 Northern Hemisphere RSV seasons and a median follow-up of 17.8 months, efficacy against RSV-LRTD in patients receiving a single dose (67.2%; 97.5% CI, 48.2%-80.0%) was similar to that noted with revaccination 1 year apart (67.1%; 97.5% CI, 48.1%-80%).44 Recently, a third phase 3 trial (NCT05590403) evaluating RSVPreF3 OA in adults aged 50 to 59 years showed positive results, and the agent became the first RSV vaccine to be granted an extended indication for use in adults aged 50 to 59 years who are at increased risk of RSV-LRTD.45-47
Regarding the safety of RSVPreF3 OA, vaccine adverse events (AEs) noted in clinical trials most frequently (≥10%) included injection site pain (60.9%), fatigue (33.6%), myalgia (28.9%), headache (27.2%), and arthralgia (18.1%).9,35 Other notable events in the clinical trial or in postmarketing surveillance included atrial fibrillation (RSVPreF3 group, 11 patients; placebo group, 8 patients) and Guillain-Barre syndrome (GBS) (postmarketing surveillance from the FDA, < 11 patients).48,49
RSVpreF (Abrysvo; Pfizer)
RSVpreF was FDA approved shortly after RSVPreF3 OA and demonstrated similar rates of efficacy in preventing RSV-related LRTD.35,36,50,51 In a phase 3, double-blind trial (NCT05035212), 17,215 adults at least 60 years of age from 240 international sites were randomly assigned to receive 1 dose of RSVpreF vaccine, and 17,069 similar participants received placebo. Vaccine efficacy was 66.7% (96.66% CI, 28.8%-85.8%) against RSV-LRTD defined by 2 or more symptoms and 85.7% (96.66% CI, 32%-98.7%) against RSV-LRTD defined by 3 or more symptoms.36 In a recent phase 3 trial (NCT05842967) investigating safety and efficacy of RSVpreF in adults aged 18 to 59 years with RSV risk factors, investigators reportedly found positive results that are anticipated to be submitted for regulatory evaluation.52,53
RSVpreF was relatively well tolerated; the most commonly reported (≥10%) AEs included fatigue (15.5%), headache (12.8%), pain at injection site (10.5%), and muscle pain (10.1%).8,36 As with RSVPreF3 OA, GBS was reported rarely in the clinical trial (n=1) and during postmarketing surveillance (n=13).36,48
Ongoing postmarketing surveillance is expected to provide more insight for both vaccines.
mRNA-1345 (mRESVIA; Moderna)
The mRNA-1345 vaccine was evaluated in an ongoing, phase 2/3 trial (NCT05127434) in adults at least 60 years of age. In this study, among 35,541 participants from 22 countries, 17,793 participants were randomly assigned to receive 1 dose of mRNA-1345, and 17,748 received placebo.37,54 Vaccine efficacy was 83.7% (95.88% CI, 66.0%- 92.2%; P < .001) against RSV-LRTD as defined by 2 or more symptoms and 82.4% (96.36% CI, 34.8%-95.3%; P = .008) against RSV-LRTD defined by 3 or more symptoms.37 The most commonly reported AEs (≥ 10%) in the mRNA-1345 group included injection-site pain (56.3%), fatigue (31.0%), headache (27.0%), myalgia (25.9%), arthralgia (21.9%), axillary underarm swelling or tenderness (15.4%), and chills (11.6%).38 Serious AEs were rare in both groups, with no cases of GBS reported in either group and 2 cases of acute pericarditis that were considered unrelated to the injection.37 After its recent FDA approval, mRNA-1345 is expected to be available for the 2024-2025 RSV season in the United States.34
MANAGED CARE CONSIDERATIONS
Now that they are approved, these efficacious vaccines for RSV-related LRTD must remain accessible to the population most likely to benefit from them. In an economic model from Herring et al, the anticipated clinical and economic benefits of RSV vaccination in older adults included reductions in hospitalizations and deaths attributable to RSV infection, highlighting the need for widespread availability and coverage of available prevention strategies.55 The importance of preventing RSV-related LRTD cannot be understated, but a vaccine can only be as effective as its uptake—and uptake may be impeded by a lack of public awareness about RSV severity and/or vaccine availability and preexisting time constraints.56
Because RSV infection is often associated with infants, health care providers and patients of older age or with cardiopulmonary risk factors must be educated about the possible severity of RSV infections and the efficacy of preventative vaccines. Media messaging surrounding influenza and COVID-19 has heightened patient awareness about circulating respiratory viruses. With RSV infection now returning to previous seasonality trends, more transparency surrounding local prevalence of RSV cases should be reported for public awareness.19 Health education campaigns such as Sideline RSV that target older adults and include patient-centered language may increase public awareness.57 Phone calls, emails, and text message reminders to patients should also be considered.58
Health care professionals can also be better educated about prevention of RSV infection. In a study by La and colleagues evaluating RSV implementation plans among vaccine policymakers and immunization coordinators, education surrounding RSV vaccination was believed to be a barrier, and pharmacist education was considered a top priority.58
Limited resources and time constraints among health care professionals continue to be barriers to vaccination.56 Appropriate resources are essential for successful RSV vaccine administration, particularly during projected peak times when vaccine demand may be higher. Leverage of the electronic medical record or creation of automated alerts for patients meeting certain criteria may offset in-office screening time.
From a payer perspective, ensuring coverage of vaccines in multiple settings (eg, outpatient offices and pharmacies) may offer more opportunities for patient education, particularly in rural areas where patients may have few regular interactions with health care professionals. Reassuringly, in the previously described survey by La and colleagues, 88% of organizations reported covering newly recommended vaccines when the CDC provides updated recommendations, which is critical in ensuring timely and affordable access to RSV prevention.56 As evaluations of currently approved vaccines continue for use in younger, at-risk populations, ongoing consideration of expanded RSV vaccination coverage will be of critical importance to ensure timely access with minimal out of-pocket costs for patients likely to receive the most benefit.
CONCLUSION
RSV is a common cause of respiratory infections with the potential for serious clinical and economic impacts, particularly in adults who are older, have certain medical conditions, or reside in nursing homes or long term-care facilities. Recently approved RSV vaccines have shown promise in reducing the rate of RSV-related LRTD in patients 60 years or older or aged 50 to 59 years at high risk; they should be recommended for patients 75 years or older and adults aged 60 to 74 years who live in nursing homes or are at increased risk of severe RSV infection. Education, adequate resources, and expanded coverage of RSV vaccines remain prudent means of ensuring access of high-efficacy prevention strategies for patients at highest risk of complications form ARIs.
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