Exploring the Potential Impact of RSV Vaccines in the Adult Population

Respiratory syncytial virus (RSV) causes respiratory infections in all age groups but is of particular concern in children younger than 5 years and adults older than 65 years.¹ Two vaccines were approved in May 2023 for the prevention of RSV in older adults.^2,3 Therefore, health care providers need to start preparing to vaccinate this population this fall. In a recent AJMC Peer Exchange, experts who specialize in treating patients with RSV were joined by professionals from the insurance industry to discuss the impact of RSV infections in the adult population, managing infections, and addressing potential barriers to the introduction of RSV vaccines in the market. The session was moderated by Adam C. Welch, PharmD, MBA, FAPhA, pharmacist and independent vaccine consultant for ETSU Health in Johnson City, Tennessee.

Disease Burden

RSV infection is a leading cause of acute respiratory tract infections, with children younger than 5 years, older adults, and high-risk adults being the most affected.^1,4,5 In 2015, an estimated 14,000 in-hospital deaths were associated with RSV-related acute respiratory illness. RSV infection in adults has a variable clinical course, with severity ranging from mild respiratory symptoms to severe lower respiratory tract infection. Furthermore, immunity to RSV diminishes over time, which can lead to recurrent infections.^4,5

In countries with temperate climates, such as the United States, RSV has a seasonal incidence, circulating throughout winter and peaking in December and January. RSV has 2 genotypes, A and B, and in general, 1 of the 2 predominates in a single season with annual alternations.⁴ The importance of RSV as a common cause of respiratory illness in adults is increasingly being recognized. In fact, infections with RSV represent up to 12% of medically attended cases of acute respiratory illness.⁴ A recent meta-analysis found a seasonal RSV incidence of 16.11 cases per 1000 persons per year, with a higher incidence among hospitalized patients. The proportion of RSV cases among cases of respiratory infection was estimated to be 4.66% in older adults and 7.03% in high-risk adults, with the latter group also experiencing severe outcomes more frequently. This worse trend for high-risk adults was also seen in the hospitalization rate, which was 32.82%, with an intensive care unit (ICU) admission rate of 26.74%. In comparison, older adults had a hospitalization rate of 24.28% and an ICU admission rate of 5.01%. Furthermore, the estimated case fatality proportion was also higher in high-risk adults at 9.88% compared with 8.18% in older adults.¹

Transmission and Pathogenesis

RSV is mainly transmitted when large nasopharyngeal secretion droplets from infected individuals come into contact with mucous membranes of uninfected individuals after close contact or by self-inoculation through touching contaminated surfaces. Infection control strategies include prompt case finding, widespread screening, restriction of visitors, and mask wearing.⁴ RSV replicates almost exclusively in the highly differentiated ciliated cells in human airways, resulting mainly in superficial damage to the airway lining; therefore, RSV itself is not cytopathic. However, this damage to the airway predisposes the patient to secondary bacterial infections and provides RSV with a mechanism to evade systemic immunity by protecting it from exposure to dendritic cells.⁴ The severity of the disease is determined by the degree of inflammation of the upper and lower respiratory tracts, caused by the viral load. Recent evidence suggests that slow viral decay and higher overall viral exposure are associated with more severe disease.⁴ Cytotoxic T cells and neutralizing antibodies mediate protection against infection and RSV clearance. However, RSV evades or suppresses memory B cells as well as the development of mucosal IgA memory responses in adults, allowing it to reinfect the host. In individuals in whom RSV manages to evade protection, CD8 T cells play a critical role in viral clearance. This leaves patients who are immunocompromised and older adults, who have a less robust immune system, at a higher risk for RSV infection.⁴

Complications and Risk Factors

Most adult patients experience mild to moderate clinical disease because they have likely been exposed to the virus before and have some immunity. However, some patients develop more severe disease, including progression to viral pneumonia, the most frequent complication. Risk factors for severe disease include Down syndrome, compromised immunity (including for patients receiving chemotherapy or chronic immunosuppression for connective tissue disease/vasculitis), underlying lung disease (especially asthma and chronic obstructive pulmonary disease [COPD]) or heart disease, older age, frailty, living in a long-term care facility, and living at high altitude. The greatest burden is seen among patients with immunosuppression, especially recipients of hematopoietic stem cell transplants and lung transplants, with an incidence rate of 12% to 16%.^1,4 Importantly, RSV infection is associated with significant sequelae that go beyond the acute hospitalization episode.⁵

Additionally, several genetic markers have been associated with a higher risk for severe disease. These markers include polymorphisms in cytokine- and chemokine-related genes such as IL-4 and its receptor, IL-8, IL-10, IL-13, and CCR5 and polymorphisms in genes associated with virus cell surface interactions or cell signaling such as TLR4, CCR1, and surfactant proteins A and D.⁴

Diagnosis and Treatment

RSV infection is not clinically distinguishable from other respiratory viruses, and diagnosis can be made through serology, cell culture, antigen detection test, and real-time polymerase chain reaction (RT-PCR).^4,5 There are no formal guidelines for the management of RSV in adults, and the standard of care is limited to supportive care with bronchodilators, supplemental oxygen, intravenous fluids, and antipyretics.^4,6 Emerging drug treatments include fusion inhibitors such as GS-5806 (presatovir), RV521, BTA-9881, BTA-585 (enzaplatovir; failed to meet viral end point), AK0529, and JNJ-53718678; nonnucleoside agents PC786, EDP-938, and JNJ-64417184; the nucleoside analogue ALS-00817184 (lumicitabine); the nanobody ALX-0171 (development program stopped); and the small interfering RNA ALN-RSV01.⁴

Stakeholder Insights

The prevailing perception is that RSV “is really a pediatric condition” that does not affect older adults, Welch said. However, as Laurene Mascola, MD, MPH, a physician and immunizations and vaccines policy consultant at the Los Angeles County Department of Public Health in California, indicated, “all persons of all ages, both healthy and with underlying conditions, are at risk for this disease, although the morbidity is greatest in those [younger than] 2 [years] and also those older than 65 [years].” Mascola explained that as we get older, so do our T and B cells, and we see a decrease in the number and function of T cells. This is known as immunosenescence, which increases the risk for RSV and other viral diseases. Other groups of adults are also particularly affected by RSV, including those with significant comorbidities, such as those with underlying lung and heart conditions; those with immunodeficiencies; those with frailty; those living in congregate living facilities; those living in socially and economically disadvantaged neighborhoods; and those with limited access to care.

“A lot of adults are not familiar with RSV,” Wanda Filer, MD, MBA, physician and chief medical officer at VaxCare in Orlando, Florida, said. She explained that RSV spreads through respiratory droplets and can progress from an upper respiratory infection to bronchitis, tracheobronchitis, or pneumonia. Asymptomatic individuals can also spread the disease. Although testing for RSV has increased recently, enhancing our understanding of its prevalence, accurate testing can be difficult and expensive, potentially posing issues with insurers.

The annual prevalence of RSV infection in adults is about 5% to 7.8%, with the CDC estimating that 60,000 to 160,000 adults are hospitalized yearly because of this disease. Mortality rates increase with age, starting around 4% for those aged 65 years and rising to 10% for adults with severe frailty. Filer and Marty Feltner, PharmD, pharmacist and director of pharmacy at Senior Rx Care Pharmacy of Nebraska in Lincoln, agreed that the burden of RSV illness is likely higher than what has been reported. “We really don’t know the prevalence of RSV in our community and in our long-term care settings right now. The virus is very similar, in clinical presentation, to influenza [or] COVID-19. So we really need to start testing for all 3, especially in long-term health care facilities,” Feltner said. Mascola added that “most states don’t have RSV as being a reportable condition,” which underlines the lack of accurate information about the true incidence and prevalence of the disease. Another aspect to keep in mind is that RSV reinfections are very common, particularly in long-term care and senior living communities, necessitating preventive measures such as isolation of infected individuals and maintaining hand hygiene, Feltner explained.

Filer discussed the symptoms of RSV, which can include sore throat, cough, fatigue, and head and nasal congestion. “I think people underestimate the impact in adults—especially the older adult, the adult who has COPD, maybe an adult who’s had a bone marrow transplant. The likelihood of them becoming very ill, requiring ICU, possibly requiring ventilatory support, being on a respirator, and even death, is extremely high,” she said. Although most patients survive the disease, many are left with a permanent deterioration in lung function. This deterioration is especially notable in patients whose lung function was previously limited, such as those with COPD, in whom even a nonserious infection will have a detrimental effect. “I think it speaks to the power of prevention and the opportunity to keep these people from getting sick. Patients who are in the ICU [with RSV], even those who [eventually] go home and recover, are still typically in the ICU longer than a patient [with influenza]. They’re often more likely to be on a ventilator; the costs associated with their care and the long-term costs of the sequelae of what they’ve been exposed to really mount up quickly,” Filer noted.

Abby Lynne Singleton, PharmD, BCPS, a senior pharmacist at Highmark Inc in Pittsburgh, Pennsylvania, talked about the drivers of health care resource utilization in patients with RSV. “Definitely some of the drivers [are] keeping patients healthy, preventing morbidity and mortality,” she said. As such, the focus should be on prevention both to keep patients healthy and to reduce costs. An RSV vaccine would help with both objectives.

Overview of the Current Vaccine Landscape

Some antibody-based therapies exist for preventing RSV, including monoclonal antibodies, RSV immunoglobulins, and inhaled nanobodies. For example, palivizumab is an RSV-specific monoclonal antibody approved by the FDA for pediatric patients at high risk of RSV disease. It has also been used successfully to prevent an outbreak of nosocomial RSV transmission in adults.⁴ However, no antibody-based therapies have been approved for adults.

Whereas initial efforts to develop a vaccine for RSV were unsuccessful, dozens of recent candidates have shown promise, including 2 recently approved vaccines, RSVPreF3 OA and RSVpreF, both targeting the RSV F protein.^2-4 With these approvals, the manufacturers, payers, and health care providers need to start getting ready for widespread vaccination efforts later this year.

The goal of RSV vaccination is to prevent severe disease and its subsequent complications in older and high-risk adults. The development of the adult RSV vaccines was more complex than that for the pediatric population because the immunologic factors required to supplement preexisting RSV immunity in older individuals were not well understood and the immunologic pathways leading to severe disease are likely multifactorial and more nuanced than in infants.4 Nevertheless, 2 adult RSV vaccines have now been approved.

Stakeholder Insights

A significant number of patients initially given a diagnosis of the common cold can develop serious respiratory complications, which underscores the importance of an RSV vaccine. The typical seasonality for RSV and influenza infections peaks in winter, but COVID-19 has altered these patterns. With society returning to normal, typical seasonal trends are expected to resume, Filer and Singleton said. However, this may complicate vaccination efforts because the schedule for adults may include up to 5 vaccines annually, which providers will have to navigate, Welch explained.

Feltner added that “from a pharmacy perspective, we could be doing all 3 vaccinations [RSV, influenza, and COVID-19] during our influenza season, which will be a huge challenge in the pharmacy and in the health care community as well.” This means that we are moving to an adult platform for vaccines in the fall, Mascola explained. “Usually, we didn’t think of adults as having an established routine for getting vaccinations, but now we’re looking at at least 3 vaccines every fall season. With pneumococcal vaccine, [influenza] vaccine, COVID-19 boosters, and now maybe even RSV, we’re actually looking at 4 vaccines that adults might need to be getting every fall season.” Filer agreed that this will be a challenge, and “one of the things we don’t know yet is, what can we coadminister? What do we need to stagger? A lot of information remains to be determined.”

Although incidence rates are expected to go back to normal this year, early peaks are still possible, and it is important that payers are proactive in preparing for that eventuality, Singleton said. The Peer Exchange took place before the FDA approved the 2 vaccines, so he expressed hope that the approvals would come soon to allow payers to start preparing for coverage, enabling patients to get the vaccines as soon as possible.

All stakeholders were optimistic about the forthcoming RSV vaccines, despite the vaccine fatigue noted among the public. An important part of the strategy to combat this is to emphasize that RSV vaccine approval was not expedited and that the RSV virus is more stable than the influenza viruses or SARS-CoV-2, which may increase public acceptance. A concerted effort by all health care stakeholders to promote vaccination and appropriate language use is crucial to drive acceptance.

For example, a key message is that vaccinated individuals protect the individuals they come into contact with, which is a familiar message that is well received for other diseases. Health care professionals have to prioritize patient education on prevention during visits, Filer said. Using technological solutions such as text messages for appointment reminders may also help increase vaccine uptake. Finally, it is also important that vaccines are available in contexts that patients find convenient and comfortable, be it the clinic or a pharmacy.

“We also make sure that you teach providers how to give a strong personal recommendation: ‘This vaccine is meant for you. I’ve had this vaccine myself. I want you to get it. I know what’s wrong with you. I’ve [managed] your COPD. I don’t want you to fall prey to this particular virus,’ ” Filer said. The other panelists agreed, with Mascola saying that “it takes a team to vaccinate a patient” and that “the data have shown that if health care providers recommend a vaccine, people are more likely to get it.” Education about this must reach the whole team, not just the physician. Feltner added that pharmacists, pharmacy technicians, and all other pharmacy workers can play important roles in identifying patients who may benefit from vaccines.

Filer emphasized that the ultimate goal is to keep patients healthy and out of hospitals while reducing complications and mortality. To facilitate this, ensuring affordable access to vaccines is key. Lastly, Singleton explained that although payers do not want to appear to be promoting certain therapies, they can play a pivotal role in aiding patients’ decision-making process about getting vaccinated and identifying potential areas of concern that should be discussed with health care providers.

Clinical Trials Surrounding Effectiveness of RSV Vaccines

Approval of RSVPreF3 OA was based on the results from the phase 3 AReSVi-006 clinical trial (NCT04886596), which demonstrated 82.6% efficacy against RT-PCR–confirmed RSV-related lower respiratory tract disease, 94.1% efficacy against severe RSV-related lower respiratory tract disease, and 71.7% efficacy against RSV-related acute respiratory infection.⁷ RSVPreF3 OA contains the RSV F protein stabilized in its perfusion conformation, which exposes epitopes targeted by neutralizing antibodies. The AS01E-adjuvanted formulation was selected for further development based on its lower reactogenicity and was used in the clinical trial.⁷

Similarly, the approval for RSVpreF was based on the results from the phase 3 RENOIR clinical trial (NCT05035212), which showed efficacy rates of 66.7% against RSV-associated lower respiratory tract illness with at least 2 signs or symptoms, 85.7% against lower respiratory tract illness with at least 3 signs or symptoms, and 62.1% against RSV-associated acute respiratory illness.⁸ The bivalent RSVpreF vaccine contains stabilized prefusion F glycoproteins from the 2 antigenic subgroups (A and B).⁸

Stakeholder Insights

The costs of an RSV infection encompass both tangible and intangible aspects, such as missed time at work and with family and potentially permanent sequelae, Filer noted. Highlighting the seriousness of RSV, Filer and Welch pointed out that between 10% and 31% of hospitalized patients with RSV end up in the ICU. This burden, already significant, is likely underreported and has implications for payers and health care systems’ budgets, Singleton added.

Welch and Feltner underlined another cost associated with RSV infections: the strain on health care systems, further exacerbated by nationwide staffing shortages. The cost sensitivity of patients and the uncertainty of insurance coverage for RSV vaccines is another challenge, Filer and Feltner pointed out. It’s crucial that the vaccines are covered because they can save both lives and money, Filer stressed. However, the exact mode of coverage through Medicare Parts B or D and the implications for patients remain uncertain. This is particularly true for patients aged 60 to 65 years, for whom the vaccine is recommended because of comorbidities but who are not covered by Medicare. It is not clear whether insurers will pay for the vaccine.

Singleton explained that Medicare can be very confusing to navigate: “Currently Medicare Part B covers [influenza], pneumonia, and hepatitis B vaccines, whereas Medicare Part D typically covers all commercially available vaccines that need to prevent illnesses, [such as] the shingles vaccine and the [tetanus, diphtheria, and pertussis] vaccine.” However, she is optimistic that patients with Medicare will be able to get access to the vaccines. Filer added that if the RSV vaccine is covered by Medicare Part D rather than Part B, it may present some challenges in terms of access. Therefore, advocates are trying to have this vaccine be covered by Medicare Part B, which would grant easier access for patients and providers. Under Part B, Mascola explained, patients could get the vaccine in more places, which is especially important for more disadvantaged populations.

Mascola noted that the current treatment for RSV infection primarily involves supportive therapies, with no definitive treatment for adults. The supportive therapies include hydration, oxygen supplementation, chest percussion, antipyretics, bronchodilators, and corticosteroids. Antibiotics are also used for patients who develop secondary pneumonia. Additionally, early-phase studies are testing the use of antiviral agents and monoclonal antibodies, but these haven’t progressed to phase 3 trials. This highlights the importance of testing because RSV does not have any approved treatments, unlike both COVID-19 and influenza.

That’s why “prophylaxis is really important in RSV to help control the costs and the clinical burden that this infection may have,” Welch said. He also pointed out that economic models predict a cost-saving value of the RSV vaccines, but more research is needed. The vaccine may need to be administered only every 2 years, as suggested by phase 3 clinical trial data, which would reduce costs but increase the need for robust reminders and state immunization registries.

Welch correctly predicted that the anticipated FDA approval for the RSV vaccines would come in May 2023, with recommendations by the Advisory Committee on Immunization Practices (ACIP) expected in early summer. The ACIP, an independent group of medical and public health professionals, plays a crucial role in providing vaccine recommendations for the United States, including details on timing, dosing, and age range. Once the ACIP provides these recommendations, the CDC translates these into an authoritative document published in its Morbidity and Mortality Weekly Report (MMWR). This process can take months, potentially leading to delays in vaccine distribution and insurance coverage.

Singleton underlined that payers highly value the ACIP recommendations and review newly approved vaccine data immediately. “I think payers will work really diligently to make sure that patients have access to the vaccine as soon as they can,” she said. However, she also acknowledged the need for a proactive stance from payers, given the time gap between ACIP’s approval and the MMWR publication. The conversation highlighted the rigorous, scientifically driven approach of the ACIP, with the stakeholders praising the organization’s transparency and dedication to public input. In anticipation of the upcoming RSV season, the stakeholders stressed the importance of prompt action based on ACIP recommendations, even before the MMWR’s release, to ensure an effective vaccine rollout.

Welch mentioned the importance that the timing will have this year “because we’re going to have a couple of vaccine candidates that will be indicated, approved, and recommended. But before the official publication comes out in MMWR, we’re going to have this time window [of waiting for it], and at the same time, RSV will start to peak out in the community. So we may have this overlap here where we’ll need the payers to come on board as fast as possible, and we’ll need the providers to be ready to go as quickly as possible.” Therefore, the education process and the planning for implementation and surveillance need to begin during the summer, Feltner and Mascola said. This includes the preparation of culturally appropriate reading materials to provide to patients in various languages, Filer added. She also noted the importance of communication strategies being educational rather than coercive; the latter would have the opposite effect and discourage people from getting the vaccine.

From the payer’s perspective, Singleton explained, “We’re definitely looking at the pipeline vaccines that are in development right now. We’ve been meeting with some of the payers to get some of that early information exchange and learn about some of the data that they already have. So [we’re] already thinking about those things, and we’ll be as proactive as we can when they come out.”

The hope is that with the introduction of the RSV vaccine, “we’ll see a decrease in RSV infections overall, which will just be outstanding to see. And then for those who do [contract] RSV, hospital admissions and admissions to the ICUs will hopefully decrease, and [just as] hopefully, morbidity and mortality will decrease in patients overall,” Singleton said, adding that this would decrease the overall costs for health care systems. Finally, she said, “As many barriers and worries that we have about these RSV vaccines, I think that there’s so much hope and promise with these coming out. I’m definitely excited. I’m looking forward to seeing my parents and loved ones protected by this vaccine, so I think keeping that in perspective—making sure that we’re all being proactive and doing our part to work as a team in order to make sure that patients get the access and the care that they need to prevent RSV—is so important.”

All stakeholders shared the excitement for the efficacy of this vaccine and look forward to seeing it approved and in use. “I’m very excited about this vaccine,” Mascola exclaimed. “I think we’re doing exactly what we need to be doing here…, talking about this vaccine and the fact that it has some very good efficacy results in the senior population. I think information on safety still is being gathered, especially as we do some more postmarketing surveillance. As we vaccinate more people, we’ll have more ability to talk about the safety of the vaccine, because it’s very important to look at both its safety and its benefits and risks. But right now, I’m really optimistic that we have a great vaccine that is very efficacious in preventing disease in this population, and we’ll be doing a lot of postmarketing surveillance to ensure its safety.”

References

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2. FDA approves first respiratory syncytial virus (RSV) vaccine. News release. FDA. May 3, 2023. Updated May 4, 2023. Accessed June 7, 2023. https://www.fda.gov/news-events/press-announcements/
fda-approves-first-respiratory-syncytial-virus-rsv-vaccine

3. U.S. FDA approves ABRYSVO, Pfizer’s vaccine for the prevention of respiratory syncytial virus (RSV) in older adults. News release. BusinessWire. May 31, 2023. Accessed June 7, 2023. https://www.businesswire.com/news/home/20230530005660/en/U.S.-FDA-Approves-ABRYSVO%E2%84%A2-Pfizer%E2%80%99s-Vaccine-for-the-Prevention-of-Respiratory-Syncytial-Virus-RSV-in-Older-Adults

4. Nam HH, Ison MG. Respiratory syncytial virus infection in adults. BMJ. 2019;366:l5021. doi:10.1136/bmj.l5021

5. Tseng HF, Sy LS, Ackerson B, et al. Severe morbidity and short- and mid- to long-term mortality in older adults hospitalized with respiratory syncytial virus infection. J Infect Dis. 2020;222(8):1298-1310. doi:10.1093/infdis/jiaa361

6. Broadbent L, Groves H, Shields MD, Power UF. Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials. Influenza Other Respir Viruses. 2015;9(4):169-178. doi:10.1111/irv.12313

7. Papi A, Ison MG, Langley JM, et al; AReSVi-006 Study Group. Respiratory syncytial virus prefusion F protein vaccine in older adults. N Engl J Med. 2023;388(7):595-608. doi:10.1056/NEJMoa2209604

8. Walsh EE, Pérez Marc G, Zareba AM, et al; RENOIR Clinical Trial Group. Efficacy and safety of a bivalent RSV prefusion F vaccine in older adults. N Engl J Med. 2023;388(16):1465-1477. doi:10.1056/NEJMoa2213836