Prevention Strategies for RSV Infection in Infants

Respiratory syncytial virus (RSV) causes acute upper and lower respiratory tract infections in people of all ages. RSV is usually associated with upper respiratory symptoms; however, infants and children are more likely to develop lower respiratory disease during primary infection. Symptoms in children usually begin with rhinorrhea and decreased appetite, followed by cough, fever, and wheezing, and symptoms may progress to include respiratory distress and lethargy.RSV is the most common reason for hospitalization in infants and is responsible for a large burden of severe illness in children. Although children with prematurity, lung disease, and congenital heart disease are at increased risk of severe illness, most cases of RSV occur among previously healthy children. Approximately 30% of infants will acquire RSV, and 2% to 3% of these infants will require hospitalization. Studies estimate that RSV is associated with 15% of all office visits for respiratory tract infections from November to April, and 2.1 million children aged under 2 years seek outpatient care for RSV infections annually. Inpatient treatment may include oxygen supplementation, rehydration, and/or mechanical ventilation, the cost of which totals $709.60 million annually in the United States.Despite the high incidence and cost, current treatment options for RSV are limited and based on supportive care measures. Researchers have been attempting to develop a successful and safe infant RSV vaccine since the 1960s. Initially, a formalin inactivated RSV vaccine was developed. During a randomized control trial, the incidence of medically attended RSV infections and severe symptoms was higher in the group receiving the vaccine than the control, and 2 children in the vaccine group died upon natural exposure to RSV. Children who received the vaccine did not develop neutralizing antibody titers comparable with those who had undergone natural infection. It was concluded the formalin inactivation had altered protein epitopes, which resulted in near complete loss of neutralization sensitive antibody epitopes and potentiated disease through the formation of immune complexes in the lung. As a result, there remain lingering safety concerns regarding the administration of nonreplicating vaccines. Live-attenuated vaccines have offered potential in infants; however, developing a vaccine that balances achieving sufficient attenuation while retaining immunogenicity remains a significant challenge. Virus vectored vaccines have shown promise in phase 1 safety and immunogenicity trials; however, they remain many years away from trials in seronegative infants. Recent developments in alternative prevention strategies offer hope in reducing the burden of RSV.Beyfortus (nirsevimab-alip; manufactured by AstraZeneca AB; distributed by Sanofi Pasteur, Inc) is a human recombinant monoclonal antibody that binds to the prefusion conformation of the RSV F protein. The attachment of nirsevimab to the F protein prevents the virus from entering the cells that line the respiratory tract, allowing viral neutralization. In a randomized clinical trial, only 1.2% of infants who received nirsevimab contracted medically attended RSV-associated lower respiratory tract infection (LRTI) compared with 5.0% in the placebo group. Medically attended RSV LRTI was defined by 3 criteria: (1) RSV confirmed by polymerase-chain-reaction assay, (2) signs of lower respiratory tract disease, and (3) signs of severe respiratory disease. Overall, nirsevimab was 74.5% effective in preventing medically attended infection.The US Food and Drug Administration (FDA) approved nirsevimab in 2023 for the prevention of RSV in infants and children aged up to 24 months. Shortly following approval, the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP) recommended nirsevimab for infants and children meeting criteria. Nirsevimab is recommended for all infants aged less than 8 months starting their first week of life if the following criteria are met: (1) it is just before or during RSV season (October through March, although this time frame may vary geographically); and (2) the mother did not receive a RSV vaccine during pregnancy, the mother’s RSV vaccination status is unknown, or the infant was born less than 14 days after maternal vaccination. Children with increased risk conditions should also receive a dose during their second RSV season. Increased risk conditions defined by the ACIP are listed in Table 1.The dosage of 50 mg administered intramuscularly (IM) is recommended for infants who weigh less than 5 kg, and 100 mg IM is recommended for infants exceeding this weight limit. Two 100 mg injections administered simultaneously are recommended for children aged between 8 and 19 months who meet criteria for administration during their second season. Possible adverse effects include injection site reactions and rash. Contraindications include severe allergic reactions to nirsevimab or any of its components.In general, previous infection, even during the same RSV season, should not be considered a factor in determining nirsevimab eligibility because RSV infection does not confer long-lasting immunity. Children who received palivizumab in their first season are eligible for nirsevimab in their second season if they meet the increased risk criteria. Palivizumab should not be administered if a child receives nirsevimab during RSV season because a single dose of nirsevimab offers protection for at least 5 months. Children can receive 1 dose of nirsevimab if they have received less than 5 doses of palivizumab during the RSV season.According to the AAP, private-sector cost for nirsevimab is approximately $520 per dose. Due to unprecedented demand for nirsevimab after its approval, there was a shortage during the first RSV season it was available (Winter 2023–2024). Nirsevimab developers are working on increasing the supply for the Winter 2024 to 2025 season.In contrast to nirsevimab, which is offered for all infants, Synagis (palivizumab; manufactured by Swedish Orphan Biovitrum AB) is cost effective for specific populations of children. Palivizumab is a humanized mouse recombinant monoclonal antibody, which was approved for use in 1998. It also binds the F protein, giving it neutralizing and fusion inhibitory activity; however, it has a significantly shorter half-life compared with nirsevimab. In a randomized clinical trial, it was found that children 35 weeks gestational age or less and children with bronchopulmonary dysplasia who received 5 monthly injections of palivizumab had a 55% relative reduction in hospitalization due to RSV compared with the placebo group.Palivizumab is recommended for the following populations when aged less than 12 months at the beginning of RSV season: (1) infants born at or before 28 weeks and 6 days gestation, (2) infants with chronic lung disease, and (3) infants with hemodynamically significant congenital heart disease. It is also recommended for children aged up to 2 years who have chronic lung disease of prematurity that requires therapy. Limitations include the need for monthly administration and the cost. The average cost of palivizumab treatment during the 2016 to 2017 season ranged from $3221 to $12 568 (this wide range is due to differences in birth months, which determine the number of doses administered per season).Alternative strategies for preventing RSV in infants include maternal vaccination during pregnancy. Abrysvo (RSV vaccine; manufactured by Pfizer Inc) is approved for administration to pregnant females between 32 0/7 and 36 6/7 weeks of gestation to prevent RSV LRTI in infants. Although months may vary geographically, administration should occur between September and January. Abrysvo contains RSV prefusion F glycoprotein from subgroups A and B, thus inducing an immune response in the recipient after injection. Randomized clinical trial results showed 81.8% vaccine efficacy within 90 days after birth and 69.4% vaccine efficacy within 180 days after birth in preventing medically attended severe RSV-associated lower respiratory tract illness in infants born to mothers vaccinated with Abrysvo vs mothers that received the placebo. Infant protection is expected to wane due to decreasing concentration of transplacentally acquired maternal antibody over time. Currently, there are no data regarding the efficacy of the first lifetime dose to protect infants born after subsequent pregnancies. Possible side effects for neonates include low birth weight (5.1% Abrysvo vs 4.4% placebo) and jaundice (7.2% Abrysvo vs 6.7% placebo). The price range is estimated between $305 and $320 per dose. Abrysvo and 2 additional vaccines (Arexvy manufactured by GlaxoSmithKline Biologicals and mResvia manufactured by Moderna) have also been approved for the prevention of severe RSV in patients aged 60 years or older.RSV in infants and children is associated with a substantial health and economic burden. Treatment remains supportive. The introduction of antibody products for infants and vaccination for expectant mothers offer promising data in protection from RSV. Although palivizumab was approved in 1998 for high-risk infants for the prevention of RSV, it has significant limitations related to cost, the need for monthly administration, and current qualifying conditions. Both nirsevimab for infants and the RSV vaccine for expectant mothers promise more widespread protection. These developments could remarkably alter the current burden of RSV disease morbidity and mortality. Logistics, including cost, distribution, and parental acceptance and uptake, remain barriers to widespread use.Comments: This In Brief reminds me of the marvels of scientific discovery and continued research to address critical health care issues. I still remember the licensure of palivizumab by the FDA in June of 1998. While it is so important to have a strategy for RSV prevention for those infants at highest risk, the process of identifying those eligible infants at high risk, the high cost of doses of medication, and challenges for infants to receive monthly doses over a 5-month period required vigilant medical staff and quality improvement initiatives to have effective ways to make this prevention feasible. A major limitation was that it was only available to infants who met high-risk eligibility requirements, and epidemiologic data have shown that RSV infection can affect infants without high-risk conditions. Great progress has been made in the development of a human recombinant monoclonal antibody, which is available to all infants and can be administered 1 time per RSV season with special considerations for an additional dose the subsequent season for those infants who are considered at high risk. While it is very exciting to have a vaccine for pregnant women and older populations, my hope is that a vaccine for infants and children will be available soon. Again, we are so fortunate as a population to benefit from the public health measures and vaccine development that save children’s lives.Janet Serwint, MDAssociate Editor, In BriefWe would like to thank Dr Matthew Thomas, Pediatric Infectious Disease Specialist, for his thoughtful review and editing of this article.