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Immunizations for respiratory syncytial virus (RSV) were newly licensed and recommended for 3 populations in the US in 2023, marking a historic turning point in the prevention of RSV illness in both young children and older adults. First discovered in 1956, RSV has long been recognized as a leading cause of acute respiratory illnesses in young children, resulting in an estimated 58鈥�000 to 80鈥�000 hospitalizations in children younger than 5 years of age each year in the US, with infants at greatest risk of hospitalization.¹ Respiratory syncytial virus has also been increasingly recognized as a cause of severe acute respiratory illness in older adults and is estimated to cause 60鈥�000 to 160鈥�000 hospitalizations and 6000 to 10鈥�000 deaths annually among adults aged 65 years or older in the US.² Until 2023, only palivizumab (a monoclonal antibody requiring monthly dosing) was available for RSV prevention for eligible infants and young children with certain underlying conditions that increase risk of severe RSV illness.

The US Centers for Disease Control and Prevention now recommends protecting all infants against RSV-associated lower respiratory tract infection during their first RSV season through either the maternal RSV vaccine (Abrysvo [Pfizer]) given to pregnant people or infant receipt of nirsevimab (a long-acting monoclonal antibody). The maternal RSV vaccine is recommended for pregnant persons at 32 to 36 weeks鈥� gestation using seasonal administration (ie, September through January in most of the continental US) to protect infants after birth through transplacental transfer of maternal antibodies. Nirsevimab is recommended for infants younger than 8 months of age entering their first RSV season and for some children aged 8 to 19 months with certain high-risk conditions entering their second RSV season. For adults aged 60 years or older, 2 RSV vaccines (Arexvy [GSK] and Abrysvo [Pfizer]) are recommended to prevent RSV lower respiratory tract infection.

All 3 newly licensed RSV immunization products were efficacious in preventing severe RSV illness in prelicensure trials.^1,3-5 Postlicensure studies are needed to corroborate findings from these trials in real-world settings and in populations underrepresented in the prelicensure trials (eg, adults with immunocompromising conditions or frailty and older age groups among adults aged 鈮�60 years).

Observational studies of real-world immunization effectiveness typically compare the frequency of the illness outcome among persons who were immunized vs those who were not (cohort design) or the frequency of immunization among persons with the illness outcome vs those without the outcome (case-control or test-negative design). In both approaches, uptake of the immunization in the population must be sufficiently high to allow for an effectiveness evaluation. Immunization and outcome status also must be accurately identified. In addition, differences in the characteristics of immunized and unimmunized persons that might be associated with risk of the illness outcome must be addressed in analyses to optimize validity.

The early introduction phase of newly licensed RSV immunizations in the US poses multiple challenges to the assessment of real-world effectiveness and impact. Low immunization uptake among the recommended groups during the 2023-2024 season may hinder assessments of immunization effectiveness using traditional observational study designs. As of February 2024, uptake of the maternal RSV vaccine among eligible pregnant persons was estimated to be 18%, uptake of nirsevimab among infants younger than 8 months of age was 41%, and uptake of RSV vaccines among adults aged 60 years or older was 22%.⁶

In addition, there may be differential uptake within groups recommended for immunization, with some subgroups more likely to be immunized than others. For example, among infants and young children, differential uptake of nirsevimab during the 2023-2024 season may have occurred because of early nirsevimab shortages. Similarly, among adults aged 60 years or older, current recommendations use a shared clinical decision-making framework informed by both the patients鈥� characteristics, values, and preferences and the health care professionals鈥� clinical discretion.² For both older adults aged 60 years or older and pregnant people, vaccination may also occur more frequently in retail pharmacy settings than for other routine vaccines (eg, because of the cost of stocking vaccines and insurance reimbursement mechanisms). Collectively, factors influencing differential uptake within groups recommended for immunization could lead to increased uptake either among those with poorer health and at greater risk of severe RSV illness (some of whom may be at greater risk of suboptimal immune responses to vaccination) or conversely, among healthier individuals who can more easily seek out vaccination. Both phenomena have been observed in studies of influenza vaccine effectiveness and can lead to bias in effectiveness estimates unless patient differences by immunization status and risk of infection are identified, appropriately measured, and addressed in the analyses.

Accurate identification of RSV immunization status may be hampered by patients鈥� or caregivers鈥� recall now that up to 3 respiratory virus immunizations (COVID-19 vaccines, influenza vaccines, and RSV immunizations) are available, and timely verification is likely to be challenging because of varying reporting requirements, jurisdictional immunization information systems, and settings for the administration of vaccines and immunizations. To assess effectiveness in young infants, accurate identification of both maternal RSV vaccination and infant immunization (including receipt of both nirsevimab and palivizumab) is important because all 3 immunizations prevent severe RSV illness. Direct comparison of the effectiveness of maternal RSV vaccination vs infant administration of nirsevimab to prevent severe RSV will require adequate use of both strategies in the same source population, standardized outcomes, and rigorous analytic methods to address differences between infants with maternal RSV vaccination exposure vs infant receipt of nirsevimab.

Interpretation of early real-world estimates of RSV immunization effectiveness during the 2023-2024 season may be affected by both patterns of immunization uptake and RSV circulation. Effectiveness estimates for RSV immunization may only be generalizable to groups that had sufficient uptake to study the effectiveness. For example, if nirsevimab was largely given to infants younger than 6 months of age because of updated prioritization guidance during supply shortages, the estimates may not be generalizable to older children. In addition, protection from immunization is expected to wane, especially in the case of passive immunization of infants through maternal vaccination and immunization in infants and young children with long-acting monoclonal antibodies. Immunization effectiveness is likely to appear higher when estimated early in the season with a shorter interval from vaccination or immunization than when estimated for the full season or over multiple seasons. Two early reports^7,8 on nirsevimab from Spain and the US suggest high levels of effectiveness against RSV-associated hospitalization early after receipt (with a median interval of 6 weeks from receipt in the US analysis), but emphasize the need for additional estimates of effectiveness for a complete RSV season.

Despite these anticipated challenges, the advent of immunizations for RSV to protect infants and young children and older adults presents unique opportunities to monitor and measure their public health effectiveness and potential shifts in RSV epidemiology. Real-world studies may answer key questions about immunizations for RSV that could not be fully addressed in prelicensure trials, including (1) the durability of protection from RSV immunization; (2) whether effectiveness varies by vaccine product in older adults, strategy (maternal vaccination or infant immunization) in young infants, and risk groups (eg, those with immunocompromising conditions); and (3) whether RSV immunization protects against a broader range of outcomes than studied in the prelicensure trials.

Newly licensed immunizations for RSV have the potential to prevent substantial numbers of hospitalizations and deaths, and real-world evidence of immunization effectiveness may support eventual introduction in low- and middle-income countries where the public health benefit may be greatest. There are rare moments in public health when decades of effort toward prevention of a specific disease culminate in the introduction of new immunization products with the potential to dramatically reduce morbidity and mortality鈥攆or RSV, the real-world evidence will determine if that time is now.

Corresponding Author: Fatimah S. Dawood, MD, Coronavirus and Other Respiratory Viruses Division, US Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30307 (fdawood@cdc.gov).

Published Online: April 11, 2024. doi:10.1001/jama.2024.5859

Conflict of Interest Disclosures: None reported.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.