Since its discovery in 1956, respiratory syncytial virus (RSV) has become a leading cause of acute respiratory illness globally. By the age of two, most children have encountered RSV, experiencing anything from mild upper respiratory infections to severe, sometimes fatal, lower respiratory tract infections. In 2019, RSV was responsible for an estimated 33 million cases of acute lower respiratory tract infections, leading to 3.6 million hospitalizations and 26,300 in-hospital deaths among children under five worldwide. Additionally, RSV accounted for 101,400 deaths, with over 95% of these cases occurring in low- and middle-income countries. Infants and young children born prematurely or with certain underlying medical conditions are at higher risk for severe RSV disease. However, most hospitalized infants and young children, including those in intensive care, were previously healthy, highlighting the need for universal preventive and therapeutic strategies to reduce RSV severity.
The development of effective RSV prevention measures is crucial due to the high burden of illness. The progress of RSV vaccines faced a significant setback in the 1960s when a formalin-inactivated RSV vaccine caused fatal adverse events following natural RSV infection. Researchers later discovered that the prefusion conformation of the RSV fusion glycoprotein is highly immunogenic, accelerating the development of RSV vaccines and monoclonal antibody products. Notably, nirsevimab, an RSV-neutralizing monoclonal antibody with an extended half-life, was approved in 2022 in the European Union and the United Kingdom, and in 2023 in Canada and the United States, for preventing RSV-associated lower respiratory tract infections in neonates and infants. This approval was based on phase 3 efficacy trials.
In this issue of the Journal, Drysdale et al. present further evidence supporting nirsevimab. Their ongoing phase 3b, multicenter, open-label, two-group, randomized trial, HARMONIE, evaluates the efficacy and safety of a single intramuscular dose of nirsevimab compared to standard care (no intervention) in preventing RSV-associated hospitalizations in infants ineligible for palivizumab. Infants up to 12 months old were recruited from 235 sites in France, Germany, and the United Kingdom. These infants, born at a gestational age of at least 29 weeks and entering their first RSV season, were randomly assigned to receive either a single intramuscular injection of nirsevimab or standard care before or during the 2022–2023 RSV season. The primary endpoint was hospitalization for RSV-associated lower respiratory tract infection during the RSV season across all three countries. Secondary endpoints included very severe RSV-associated lower respiratory tract infection, hospitalization for RSV-specific lower respiratory tract infection in each country, and hospitalization for lower respiratory tract infection of any cause. Adverse events were monitored throughout the trial, with serious adverse events tracked for up to 12 months post-randomization.
The target enrollment for the study was 28,860 infants, with the primary endpoint to be assessed once at least 61 primary endpoint events had occurred. By February 28, 2023, 71 infants had been hospitalized for RSV-associated lower respiratory tract infection, and 8,058 infants had been assigned to receive either nirsevimab (4,037 infants) or standard care (4,021 infants). The higher-than-expected incidence of hospitalization for RSV-associated lower respiratory tract infection aligned with the resurgence of RSV during the 2022–2023 season.
Hospitalization for RSV-associated lower respiratory tract infection occurred in 11 infants (0.3%) in the nirsevimab group compared to 60 infants (1.5%) in the standard-care group, indicating a nirsevimab efficacy of 83.2%. This efficacy was consistent across subgroups defined by age, weight, gestational age, sex, and timing of randomization (before or during the RSV season). Efficacy varied slightly by country, with 89.6% in France, 83.4% in the United Kingdom, and 74.2% in Germany. Very severe RSV-associated lower respiratory tract infection was observed in 5 infants (0.1%) in the nirsevimab group and 19 infants (0.5%) in the standard-care group, representing an efficacy of 75.7%. Nirsevimab also showed 58.0% efficacy against hospitalization for lower respiratory tract infection of any cause. No significant safety concerns were raised, with treatment-related adverse events occurring in only 2.1% of infants in the nirsevimab group. However, the open-label trial design may have introduced bias into the safety assessment. Despite this, the efficacy and safety outcomes observed in the HARMONIE trial, conducted under real-world conditions, are consistent with findings from two previous phase 3 trials.
For over 50 years, RSV prevention options have been largely ineffective or limited to high-risk populations. The introduction of nirsevimab is exciting as it offers a practical, single-dose alternative that extends protection to all infants. Maternal vaccination is another recent option to prevent RSV infection in infants, and balancing these two strategies will be essential.
Nirsevimab presents new challenges alongside its benefits. As high-income countries begin implementing nirsevimab, active surveillance for RSV is crucial to evaluate its effectiveness and the evolution of RSV. Equally important are the “five A’s” of healthcare access—affordability, availability, accessibility, accommodation, and acceptability—especially in low- and middle-income countries, where RSV-associated morbidity and mortality are highest. Ensuring that nirsevimab reaches these vulnerable populations is not only a matter of equity but also essential to mitigate the global impact of RSV on health and society.
Halasa, N. B. (2023). RSV prevention — breakthroughs and challenges. The New England Journal of Medicine, 389(26), 2480-2481. doi:https://doi.org/10.1056/NEJMe2312934