Article highlights
- Historical Challenges: RSV vaccine development has been difficult due to the virus's complexity and lifelong reinfection potential.
- Clinical Impact: RSV leads to severe respiratory illnesses in children, causing hospitalizations and secondary bacterial infections.
- Recent Advances: In 2023, Nirsevimab-alip, a monoclonal antibody, and Abrysvo, a maternal vaccine, were approved, reducing RSV-related infections in infants.
- Challenges: RSV vaccine development faces hurdles like defining clear endpoints and addressing varying target populations. Implementing new measures involves monitoring variants and managing costs.
- Future Outlook: Ongoing research explores diverse vaccine types, aiming to comprehensively reduce RSV-related morbidity in the future.
Respiratory syncytial virus (RSV) was first identified in 1956.1 Although it was quickly recognized as an important cause of respiratory infections in young children, it has been a challenging target for vaccine development. Pediatric care providers have become familiar with the symptomatic management of RSV with only a small arsenal of preventative measures related to modifiable risk factors: handwashing, limiting contact with sick individuals during the newborn period, and breastfeeding.2,3 Although palivizumab (Synagis) has been available for high-risk infants,4 RSV causes the deaths of 10,000 individuals, including 100 to 300 children, each year in the US. The CDC estimates that 1 or 2 of every 100 children will be hospitalized with a lower respiratory tract infection caused by RSV in the first 6 months of life, making it the leading cause of hospitalization for respiratory illness. Admissions to hospitals for RSV infection are estimated at 58,000 to 80,000 per year.5 Virtually all children are infected with RSV at least once by the time they are 2 years old.5
Before the COVID-19 pandemic, RSV epidemics had a predictable beginning in the United States, starting in midfall, lasting through winter and early spring in temperate climates, with some small variation in onset in the southern United States. During the pandemic, due to pandemic measures such as physical distancing, changes in child care, and mask use, the typical season did not occur in fall 2020 or 2021; however, beginning in spring 2022, lasting through summer, and then in fall 2022, there were atypical surges in RSV infections due to many toddlers who were RSV naïve as well as a new birth cohort.6 It is anticipated that the RSV season will return to its predictable tempo in fall 2023.
Clinical manifestations
RSV replicates in the cells that line airways and disrupts those linings. Depending on which area is affected, symptoms can include rhinorrhea and congestion, cough, apnea, fever, loss of appetite, shortness of breath, lethargy, along with breathing difficulties. Specifically, RSV can manifest as an upper respiratory infection, croup, or viral otitis media, or it can cause lower tract disease, including bronchiolitis and pneumonia.7 Secondary bacterial infections can occur, including acute otitis media and bacterial pneumonia. Disease manifestations are exacerbated by the child’s immune response, which leads to local inflammation and mucus production. Their airways then become narrower and filled with excess mucus, cell debris, and fluid.8 Care includes symptom management and at times hospitalization for intravenous fluids, oxygen, or respiratory support. Additionally, babies who have RSV early in life may be predisposed to higher rates of reactive airway disease, potentially impacting them for a lifetime.8
The pipeline
The population-level impact of RSV has made it a target for vaccine development for decades. Beginning in the 1960s, RSV vaccines have been studied and trialed, with the structure of the virus driving many of these endeavors. The virus has 11 proteins, though proteins F and G have been identified as critical for the infectivity and pathogenesis of the virus. The F protein has become the preferred target in vaccine development because it has a crucial role in host cell viral entry and it is highly conserved between the 2 subtypes of RSV (RSV A and RSV B).9 This F protein exists in 2 conformations–pre and post.10 The pre-fusion (F) formation is more immunogenic. Antibodies that bind to pre-F are more efficient at neutralizing the virus.11
Challenges with making RSV vaccines are numerous.9 First, reinfection with RSV throughout life is common. Natural immunity is not complete or long-lasting, which indicates a vaccine must induce a stronger response. The mechanisms required to produce longer-lasting immunity are incompletely understood. Second, early experience with a formalin-inactivated vaccine demonstrated that infants naïve to RSV prior to vaccination then had enhanced disease on natural exposure to RSV, leading to long-standing safety concerns while also indicating the need for a purified protein approach. Third, the varied populations including infants, older children, and the elderly that would benefit from vaccination require different mechanisms of vaccination. Specifically for infants, it is critical to recognize their immature immune systems and the potential for interference by maternal antibodies. An additional consideration is determining the goal of the vaccination platform. Overall, the goal is to reduce disease severity and mortality, but there are multiple clinical end points, including reducing hospitalization, recurrent wheezing or asthma, and outpatient burden of disease. Finally, the immune correlates of protection will need to be different based on the vaccine or preventive medication used. In the background, the changing epidemiology of the virus, the need to monitor for mutations, and the lack of an ideal animal model complicate ongoing work.
Prior to 2023, only 2 pharmaceutical preventive measures were available: RSV-IGIV (RespiGam), a polyclonal immunoglobulin (IgG), and palivizumab (Synagis), a humanized IgG1 monoclonal antibody to the RSV F protein.12 RSV-IGIV was licensed in 1996 for use in children with prematurity and chronic lung disease, but not those with congenital heart disease. With several clinical complications, it was withdrawn from the market in 2004. Palivizumab was first approved by the FDA in 1998 for high-risk children. Guidelines from the American Academy of Pediatrics have evolved to ensure use is recommended only for those children identified as high risk and in whom there has been documented clinical benefit.4
With only moderate success of palivizumab due to its limited clinical indications, high cost, and labor-intensive administration, development efforts continued. Researchers recognize that a suite of prevention measures, including vaccines for the elderly, pregnant women, and older children in addition to longer-lasting monoclonal antibodies for infants, will significantly impact morbidity. There have been approximately 40 candidate vaccines evaluated in the past 10 years alone.1
Recent approvals
Nirsevimab-alip (Beyfortus), a monoclonal antibody, was approved by the FDA in July 2023 and added to the childhood immunization schedule in August 2023.13 Clinical trials indicate a 74.5% risk reduction in medically attended lower respiratory tract infections in late preterm and term infants in the first 150 days after injection.14
Use of a monoclonal antibody sidesteps some of the challenges of infant immunization by passive immunization. Nirsevimab delivers the antibodies directly to the at-risk infant. This removes the need to design a vaccine that an immature immune system can recognize, limits the time to immunity associated with the multiple doses of an infant vaccine series, and avoids the interference of maternal immunity. Timing of administration ensures infants are protected when they need it most, and durability lasts through the RSV season.15 Adverse effects observed in trials are minimal, limited to injection site reactions and rash.14
Utilizing nirsevimab has challenges. Escape variants may be able to evade neutralization by monoclonal antibodies, though use of any target other than the F protein is still under investigation.16 Additionally, this passive immunization is anticipated to provide protection for at least 5 months, approximately the length of the RSV season. Once children are older, they will be exposed to RSV and an anticipated milder illness because they will have more adept immune systems as well as larger airways, leading to better tolerance of natural infection. The shifting epidemiology of RSV disease will need to be studied and followed. Finally, there are new implementation challenges with the administration of this to a large patient population. Nirsevimab is specifically identified as a medication, not a vaccine. It has a large up-front cost to be managed by providers and concern for inadequate payment. Although it has been added to the childhood immunization schedule, facilitating coverage by the Vaccines for Children (VFC) program, approximately 90% of birth hospitals do not participate in VFC. Individual practices will need to review insurance coverage for their patient population in the first year of use and build out immunization information systems that can integrate this medication into the record.13 These implementation challenges are numerous but surmountable.
Looking ahead
In August 2023, an additional piece of the arsenal to reduce infant infections was approved by the FDA. Pfizer developed the RSV vaccine Abrysvo for use in pregnant women 32 to 36 weeks’ gestation to prevent lower respiratory tract disease (LRTD) and severe LRTD caused by RSV in infants.17 This is an RSV prefusion F (RSVpreF) vaccine that reduced the risk of severe LRTD by 81.8% within 90 days of birth and 69.4% within 180 days of birth when compared with placebo. Pregnant patients experienced pain at the injection site, muscle pain, headache, and nausea. Jaundice and low birth weight occurred at a higher rate in the infants delivered to mothers who received the vaccination when compared with placebo. Most significantly, there was an imbalance in the number of preterm births in the group of vaccine recipients compared with placebo (5.7% vs 4.7%, respectively). For this reason, the vaccine should not be administered until after 32 weeks’ gestation. This safety signal will continue to be monitored in postmarketing studies. The Advisory Committee on Immunization Practices will review this vaccine in October 2023 to provide guidance on administration.17
Beyond the introduction of nirsevimab and a maternal vaccine in 2023, there is a robust pipeline of vaccine development, including live-attenuated vaccines for pediatric patients, mRNA vaccines, and vector-based vaccines. In addition, researchers are working to understand delivery mechanisms needed for success in low- and middle-income countries.18 Although these first tools will be implemented in 2023, there will likely need to be a number of different strategies to truly reduce the morbidity associated with RSV in years to come.
Click here for more from the October 2023 issue of Contemporary Pediatrics®.
References:
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