So we now have RSV vaccines. What’s our next steps?

KEYWORDS:

• RSV
• adults
• respiratory infection
• vaccine
• elderly
• Paediatrics

1. Introduction

Respiratory viral infections have a major impact on human health and the newly approved vaccines for respiratory syncytial virus (RSV) are a welcomed addition for prevention of infection with this under appreciated pathogen. The recent SARS-CoV-2 (COVID-19) pandemic has, amongst many things, elevated awareness within medical communities and the general population about respiratory viral diseases, morbidity and mortality. In the lay community, viral respiratory diseases are often thought of as the ‘cold’ with symptoms of a sore throat, runny nose, achy muscles, cough, and perhaps fatigue. In medical communities, it has long since been known of the potential severe consequences of respiratory viral infections with influenza as an annual reminder of deaths, across all age groups, from severe disease and complications. A new reality of the COVID-19 pandemic, aside from severe acute infection and death, is the clinical phenomenon of ‘long COVID’ or persistence of recognized symptoms for prolonged periods after the acute infection has resolved. Originally long-COVID was thought to be a consequence of severe COVID in patients requiring hospitalization, however, more recently, long COVID has been reported from patients with milder disease (no hospitalization) but at a lessor frequency than seen from hospitalized patients [1]. Persistent or complicated clinical consequences are also seen with other respiratory viruses and may include myocarditis or pericarditis, central nervous system involvement, pneumonia, and post-viral secondary bacterial infections. Specifically, Respiratory Syncytial Virus (RSV) infection may exacerbate chronic obstructive pulmonary disease, congestive heart failure and the virus may cause direct tissue damage – likely mediated by the inflammatory response [2] – with long term impact. As such, ‘long’ health consequences from viral infection is not a COVID-19 only phenomena.

2. RSV microbiology

RSV belongs to the orthopneumovirus genus of the Paramyxoviridae, subfamily Pneumoviridae family in the order Mononegavirales [3]. Morphologically the virus is pleomorphic with both filamentous and spherical forms observed, however, spherical forms are more common. The nucleic acid is non-segmented, single stranded, negative sense RNA, meaning the virus carries RNA dependent RNA polymerase enzyme which is necessary for the initial steps in virus replication. The virus contains a lipid envelope, which is derived from the host cell plasma membrane during exocytosis from infected cells. Three recognized major proteins associated with the envelope include the F or fusion protein which initiates viral penetration, the G protein which is responsible for mediating attachment of the virus to host cells and the SH or short hydrophobic protein which accumulates in lipid structures of the Golgi complex during infection. A number of other structural proteins exist as well and include the N (nucleoprotein) important for nucleocapsid structure and the P (Phosphoprotein) and L (large or polymerase protein) and M (matrix) proteins important for viral replication. RSV may survive for prolonged periods (hours) outside the host and infectivity is affected by conditions such as temperature and humidity [4].

3. RSV transmission

RSV is transmitted through droplet spread when infected individuals cough and/or sneeze and from contact with nasal and throat secretions from infected patients. It can be spread from dried secretions on bedclothes, other fabrics and inanimate objects and counter tops [5]. Transmission from aerosols – while possible – seems less likely [6]. For decades, it was accepted that the usual period of contagiousness ranges from 3–8 days. In patients with weakened immunity, virus shedding can continue for up to 4 weeks (CDC.gov/respiratorysyncytialvirus) [7]. Citing methodological differences from previous studies, Munywoki et al reported longer durations of viral shedding with RSV with an average duration of 11.2 days (range 8.2–13.6 days) [8]. Interestingly, some individuals shed virus for ≥21 days, and the majority of these patients (91.7%) were symptomatic at some point during the duration of viral shedding.

4. RSV burden

Respiratory Syncytial Virus (RSV) is one of the most common seasonal viral infections seen worldwide with more than 30 million cases in children ≤5 years, resulting in < 10% hospitalization [9]. The United States Center for Disease Control (CDC) estimated that 58,000–88,000 children under 5 years of age are hospitalized due to RSV infection [10]. In 2019, there were an estimated 33 million RSV associated lower respiratory tract infections in younger children with some 95% occurring in low to middle income countries [11,12]. Children at the greatest risk for severe infection include premature infants, infants up to 1 year of age and in particular those 6 months of age or younger, children under 2 years of age with chronic lung disease or congenital heart disease, children with weakened immunity and children with neuromuscular disorders affecting swallowing or clearing of mucus secretions. At the time of writing, RSV vaccinations in children were not approved; however, the monoclonal antibody nirsevimab has been shown to reduce RSV hospitalizations and prevent RSV-associated lower respiratory tract infection and against severe RSV-associated lower respiratory tract infection in infants [13]. A maternal RSV vaccine for pregnant women has been recently approved and discussed under the section of Vaccines.

Despite available data in the peer-reviewed literature, RSV is often an underappreciated pathogen when considering severe respiratory infection requiring hospitalization in older adults. Prior to the COVID-19 pandemic, seasonal influenza was the focus of the autumn/winter vaccination campaign. This makes sense as there was an annual vaccine for Influenza A and B and influenza is a well-recognized respiratory virus associated with significant morbidity, mortality, and health care resource expenditures. With the now availability of the RSV vaccines, it will be interesting to see if in subsequent years, annual vaccination campaigns will be joint Influenza/RSV/COVID-19 promotions – particularly in vulnerable populations.

Hamilton and colleagues reported on the burden of respiratory diseases in Ontario, Canada, and compared hospitalizations and deaths for patients infected with Influenza A, RSV, and COVID-19 [14]. Considering Influenza A between September 2010 to May, 2019, 45748 hospitalizations with 3186 (7.0%) deaths were noted as compared to 24,345 hospitalizations with 697 (2.9%) deaths with RSV (same time period) and 8988 hospitalizations with 1880 (20.9%) deaths due to COVID-19. It is important to point out the time period for the COVID data was from March, 2020 to December 2020 and prior to the availability of the COVID-19 vaccines. While both the hospitalization and death numbers are lower for RSV than for Influenza A, RSV accounted for substantial costs to the health care system and, in fact, are likely higher due to hospitalized patients not having a confirmed diagnosis. In the study by Hamilton et al., risk factors for mortality from RSV included older age, males, living in a long-term care home and chronic kidney disease.

The CDC [7] estimates that between 60,000–160,000 older adults in the U.S.A. are hospitalized with RSV infections and some 6,000–10,000 die annually. Those at greatest risk include older adults (60 years or older), adults with chronic heart and lung disease, kidney and liver disorders, neurological or neuromuscular disorders, hematological disorders, diabetes, adults with weakened immunity (moderate or severe), and adults living in nursing homes and long-term care facilities. Others at risk include persons who are frail, advanced age, and those with underlying conditions which in the opinion of the health care provider might increase the risk for severe respiratory disease. Severe RSV infections may exacerbate conditions such as asthma, chronic obstructive pulmonary disease, and congestive heart failure – chronic conditions that are prevalent in various populations – including the elderly. Holman commented on the chronic disease epidemic in the U.S.A. and indicated some 50% of the American population has a chronic disease which utilize 86% of health care resources [15]. The CDC in the U.S.A. indicated 90% of the nation’s 4.1 trillion health care costs are spent on people with chronic and mental health conditions [16]. In a 2020 report ~ 17.5% of the Canadian population were classified as seniors – reaching approximately 25% by 2040 [17]. With life expectancy increasing, an average 65-year-old can expect to live an additional 21.0 years (19.5 years for men and 22.3 years for women). More women (30.9%) than men (27.7%) spent a greater proportion of their post-65-year life in an unhealthy state. Almost half of seniors in Canada perceived their health to be good despite living with chronic diseases. Perceptions of good health seems related to economic security, social connectedness, satisfaction with life and psychological well-being. As such, a person that deems themselves to be in good health may be unaware of risks associated with advancing age, infectious diseases, chronic diseases and the benefits of immunization. In 2022, 36.1% of the European Union Population aged 16 years or older reported having a long-standing illness or health problem and males reported better health than females. As such and as we know, chronic diseases are not seen only in the eldely.

Nguyen-Van-Tam and colleagues reviewed papers published between 2000–2019 for symptomatic RSV infection (and associated healthcare utilization) in developed countries for adults 60 years of age or older or those at high risk for severe infection [18]. Some 103/3429 articles met the inclusion criteria and amongst older adults RSV caused 4.66% of symptomatic respiratory tract infections in annual studies (7.03% in high-risk patients) and 7.8% in seasonal studies (7.69% in high-risk patients). The RSV-related case fatality proportion was at 8.18% (9.88% in high-risk adults). Influenza was estimated to cause an average of 389,000 respiratory related deaths which corresponded to ~ 2% of all annual respiratory deaths [19], and of these, 67% were amongst adults ≥65 years. Hansen and colleagues [20] reported on mortality associated with RSV and Influenza in the U.S.A. between the years 1999–2018 and was based on data from 50.3 million death certificates. Astonishingly, 50.1% were women and 49.9% men with a mean age at death being 72.7 years. A mean of 6549 (range 5035–7645) respiratory related deaths were associated with RSV annually as compared to a mean of 10,171 (range 393–23176) for influenza with the highest mean mortality rate/100,000 population was in adults over 65 years of age: 14.7 for RSV and 20.5 for influenza. Influenza deaths were also influenced by the strain circulating. Advances in diagnostic technology has helped to further define respiratory virus-related deaths. Season to season variability was more common with influenza than with RSV.

Juhn and coinvestigators stated that RSV positive acute respiratory infection in older adults prior to the COVID-19 pandemic was substantial! [21]. This study investigated more than 2300 adults ≥50 years in South-East Minnesota for 2 respiratory seasons between 2019 and 2021 including prior to the COVID-19 pandemic. The median patient age was 67 (range 50–98) and 59% of participants were female. The pre-pandemic incidence rate for RSV acute respiratory infections was 48.6/1000 person years with a 2.5% attack rate. Interestingly, patients with RSV (compared to RSV negative controls) reported a lower quality of life based on several parameters including physical health limitations, lower energy level or fatigue, decreased social functioning, and role limitations due to emotional problems, and some of these quality of life parameters were seen over short, intermediate, and longer terms. This study also demonstrated that a large percentage of patients with RSV-positive acute respiratory infection developed severe disease (97%) and lower respiratory tract disease (71%). Falsey et al investigated hospitalized patients from 40 centers in 12 countries over 2 RSV seasons from 2017–2019 that had acute respiratory infection [22]. The mean age of patients was 66 years and RSV positive patients were followed for up to 3 months. At 3 months post-hospital discharge, acute respiratory infection-RSV positive patients were more likely to have shortness of breath (as compared to influenza 16.1% versus 9.1%) and cough (8.6% versus 3.5%).

5. RSV maternal vaccine

An RSV vaccine is now approved for pregnant females with immunization recommended between 32–36 weeks of pregnancy; however, the clinical trial enrolled patients between 24–36 week gestation [23]. Two primary efficacy endpoints were measured – medically attended severe RSV-associated lower respiratory tract infection and medically attended RSV-associated lower respiratory tract illness in infants 90, 120, 150, and 180 days after birth. A total of 7358 pregnant women (3682 received vaccine and 3676 received placebo) were enrolled with 2840 and 2843 respectively completed the trial. A total of 3570 infants born to vaccinated mothers and 3558 born to mothers that had received placebo were evaluated. Maternal RSV vaccine reduced the risk of the baby being hospitalized or having a healthcare visit for RSV by 67.7% and 51.4%, respectively within 3 months of birth and by 56.8% and 51.3%, respectively within 6 months after birth. Maternal RSV vaccination reduced the risk of severe RSV disease (tachypnea, hypoxemia, use of high flow nasal cannula or mechanical ventilation, unresponsiveness or admission to the intensive are unit) by 81.8% and 69.4% within 3 and 6 months after birth, respectively [23].

Pain at the injection site was the most commonly reported site effect (41% in vaccine recipients vs 10% in placebo group: other side effects included muscle pain (27% vs 17%, respectively) and headache (31% vs 28%, respectively) or other adverse events within 1 month after injection (13% vs 13.1%, respectively). Regarding safety, those that received maternal RSV vaccination between 24–36 weeks of pregnancy had a higher (non-statistical) incidence of pre-term births as compared to placebo. For those that received maternal vaccine between 32–36 weeks of pregnancy, pre-term birth occurred in 4.2% of vaccinated patients compared to 3.7% of placebo recipients. Patients at high risk for pre-term birth were not included in the vaccine studies. Available data does not confirm or exclude maternal RSV vaccination and pre-term births. Hypertensive disorders occurred in 1.8% of vaccinated patients versus 1.4% of placebo recipients. Jaundice, pre-eclampsia and low birth weight (<5.5 lbs) occurred more frequently in infants born to vaccine recipient mothers. Additional studies are both ongoing and necessary.

6. RSV vaccine (elderly)

RSV vaccine efficacy was evaluated in 12,467 vaccine recipients and compared to 12,499 unvaccinated controls [24]. Patients were ≥60 years of age. The median follow-up time was 6.7 months. Overall vaccine efficacy was 82.6% with 7 RSV cases recorded in the vaccine group and 40 cases in the unvaccinated control group. RSV infection was confirmed by polymerase chain reaction (PCR) laboratory testing. Vaccine protection against severe disease was 94.1% with efficacy against acute RSV infection being 71.7%. In a second publication from the same data set, Feldman et al further reported on vaccine efficacy in patients with underlying medical conditions [25]. Of the 12,467 vaccine recipients, 39.6% had ≥ 1 coexisting medical condition as compared to 38.9% in the unvaccinated control population. While vaccine efficacy was 64.6% for patients with preexisting medical conditions, efficacy for those with ≥ 1 cardiorespiratory conditions was 92.1%, ≥ endocrine/metabolic conditions was 100% and for those with ≥ 2 conditions of interest was 92%. The overall efficacy for protection against acute respiratory infection was 81% and for the above noted groups was 88.1, 79.4 and 88.0%, respectively.

Vaccine safety was evaluated in 1757 solicited recipients. The CDC lists the following as vaccine associated side effects: pain, redness, swelling, fatigue, headache, fever, nausea, diarrhea, and muscle/joint pain. Guillian Barre syndrome was listed as a possible side-affect but the association with the vaccine remains unknown. From the safety evaluated population, pain at the injection site was reported in 60.9% of vaccine recipients as compared to 9.3% of placebo recipients. Fatigue was reported from 33.6% of vaccine recipients versus 16.1% of placebo recipients. Most reactions were reported as mild to moderate with a maximum 4-day duration with most resolving in 1–2 days.

7. Vaccination and antimicrobial resistance

Does vaccination prevent antimicrobial selective pressures and antimicrobial resistance? Intriguing question! Ripa and Mastrangelo in an excellent editorial commented on secondary infections and antimicrobial use in patients with COVID −19 – the so called ‘Elephant in the Room’ [26]. Specifically the authors were commenting on a publication by Grasselli et al reporting on hospital acquired infections in critically ill patients with COVID-19 [27]. Early reports suggested that up to 50% of patients with COVID-19 requiring hospitalization and admittance to the ICU had a hospital acquired infection with ventilator associated pneumonia being the most common. The study by Grasselli and colleagues gathered data from an ICU network on > 700 patients with severe COVID-19 and considered incidence, risk factors, microbiologic landscape, and clinical impact of secondary infections. Interestingly, 68% of the patients received antibiotics at the time of ICU admission, but after multisite diagnostic workup, only 1% of the patients had a secondary infection. Multi-drug resistant pathogens were a concern. While secondary infections at the time of ICU admission may be low, secondary infections are a legitimate concern during ICU stays. Ripa and Mastrangelo commented that the ‘vicious circle’ of antibiotic misuse, increased prevalence of colonization by multidrug-resistant pathogens, and infection and deleterious consequences for individual patients and the global ecology could be impacted by more judicious use of antimicrobials. Additionally, use of broad-spectrum antibiotics could mask microbiological investigations and complicate diagnosis of subsequent secondary infections. Clearly, vaccination (Influenza, COVID-19 and now RSV) resulting in reduced hospitalization in vulnerable populations reduces the likelihood for secondary infections and thus the need for antimicrobial use – including broad spectrum agents. By inference, immunization has a positive impact on unnecessary antimicrobial use and antimicrobial selective pressures by reducing hospitalization and ICU admission.

8. Vaccination: cost/benefit

Cost benefit analysis is an important consideration with health care resources. Are vaccination programs financially justifiable and can you measure positive and negative impacts? On an individual basis, a vaccinated person that does not become infected or is mildly infected, avoids hospitalization, complications, and treatment costs is an obvious benefit to both the individual and the system. It is likely more detailed cost-benefit analysis for RSV vaccination programs will be forthcoming but some projections now exist. The cost effectiveness of RSV vaccines in older adults was investigated by the School of Public Health at the University of Michigan [28]. In essence, the team considered the costs of the vaccine balanced against cost savings from averting RSV disease and the negative health effects from vaccine adverse events against the health benefits of averting RSV disease. With their model, it estimates that if 20% of adults ≥65 years of age in the U.S.A. were vaccinated with an RSV vaccine, over 220,000 outpatient visits 26,000 emergency room visits 22,000 inpatient stays and 1,100 deaths related to RSV would be averted over a 2 year timeframe. However, the costs of vaccination would be between $2 and $2.7 billion dollars. Wang et al reported on the cost effectiveness analysis of RSV vaccines for older adults in Hong Kong [29]. They concluded that a single vaccine dose to adults ≥ 60 appeared to gain quality adjusted life years by reducing RSV-associated events over 2 years. Cost effectiveness is highly subject to vaccine price and RSV attack rate.

Tuite et al reported on a cost benefit of the COVID-19 vaccination program in Canada using a model-based cost-benefit analysis [30]. The model estimated the number of symptomatic COVID-19 cases, hospitalizations, post-COVID conditions, and deaths in the presence and absence of vaccination. There model results indicated that the savings far outweighed the cost of vaccination and increased the net benefit by $298.1 billion Canadian dollars. The largest benefits were due to premature mortality and estimated at $220.0 billion Canadian dollars. Variables considered included direct costs (i.e. hospitalization ~$25,000.00/case; post-COVID condition ~$9700/case), indirect costs (i.e. average employment income ~$49,000.00–$59,000.00 for individuals less than 64 years of age), productivity loss, quality adjusted life years other parameters such as vaccine effectiveness and waste plus others. Utami and colleagues performed a systematic review on the economic benefits on COVID-19 vaccination by reviewing 25 studies [31]. All studies suggested vaccination to be a cost-effective or cost-saving intervention.

9. Vaccination barriers

Barriers to vaccine uptake are being recognized. RSV infections are often overshadowed by Influenza A infections (pre-pandemic) and certainly since 2020 by COVID-19 – both of which have dominate hospitalizations and mortality leaving RSV an underappreciated pathogen in elderly patients. Additionally, some health care providers think of RSV in the context of pediatric or neonatal infections [32] but with the now available maternall RSV vaccine this landscape may change. Ramirez et al rightfully identified RSV as a potential cause of community acquired pneumonia in immunocompromised adults [33]. Vaccine uptake is often associated with who or whom is paying for the vaccine. Coverage through government programs or private insurance companies facilitates uptake but uptake is less and slower when payment is by the individual. In a way, this creates a ‘catch 22’ scenario. The benefits of the vaccine as a preventative intervention reducing hospitalization and mortality in children <6 months of age and elderly patients is now known – certainly in elderly patients with co-morbidities, yet elderly patients on fixed incomes may not have the resources to pay for the vaccine. Specifically, elderly patients may have to choose between vaccines for shingles (Varicella Zoster Virus), pneumococci (Streptococcus pneumoniae) and now RSV. Certainly the cost benefit in an individual RSV vaccinated patient versus the cost of hospitalization is an easy argument. A more difficult argument from the payer (government or private insurance) point of view might be the cost benefit ratio for immunizing everyone 60 years of age or older or younger patients with significant underlying medical conditions and the reduction in hospitalizations. Should government/insurance funded vaccinations be prioritized to those 60 and over and with co-morbidities. In my opinion, this is an ethical challenge as RSV can be devastating in elderly patients without co-morbidities and now we have a vaccine that could reduce/prevent serious infection. The benefits of preventing severe respiratory tract infection in children <6 months of age and impacting on mortality or long term health benefits is a non-argument and maternal vaccinations should be widely available.

10. Further questions

The approval of RSV vaccine for clinical use raises a number of interesting questions that hopefully will be addressed by ongoing and future novel research investigations. First, it is important to continue to collect data on vaccine safety as the number of vaccinated individuals increase. Second, does vaccination for RSV (along with influenza and COVID-19) alter the epidemiology of other seasonal respiratory viruses? Third, what might be the impact of RSV vaccination on asymptomatic or mild RSV infection and how can this be monitored? Fourth, the current vaccine for elderly patients is a single shot with protection for 2 years. Will a booster shot be necessary after 2 years and what might that do for the ongoing or longer periods of protection? Should a booster shot cost the same as the primary vaccine? Fifth, would RSV vaccination – preventing early life infection – have long term benefits to children related to chronic respiratory disease (eg. asthma [34]) or immunological development [35]? Sixth, does vaccination impact lung health of children beyond infancy and does immunization in early life impact mortality in later life? Many more research questions are likely to arise and for elderly patients with comorbidities and vaccinated against RSV, do their underlying medical conditions remain more stable over time compared to unvaccinated individuals? Additionally, is long term morbidity impacted?

So, we now have RSV vaccines recommended for pregnant women, elderly patients and perhaps younger patients with significant underlying medical conditions and at risk for severe disease. What’s the next step? The phrase ‘an ounce of prevention is worth a pound of cure’ simple means that is better to prevent something from happening rather than repairing the damage from having it happen. In all instances, the cost of prevention is substantially less than the cost of repair. Vaccinations are the ‘ounce’ of prevention. Patient vulnerability exists early in life and increases with age and those with chronic diseases not only are at increased risk of severe infection but also utilize more healthcare resources. In my opinion, the next step is clear and RSV vaccine should be covered by national programs or through private insurance and not have to rely on individual patients to pay – many who may not be able to afford it. With at risk infants and an aging population, that ounce of prevention might actually be several pounds of cure.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.