New Interventions to Prevent Respiratory Syncytial Virus Disease in Infants—Time for Equitable Global Access

Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) has a global cost estimate of €4.82 billion, causing more than 100,000 deaths and over 3.5 million hospitalizations per year, mostly in infants in low-middle-income countries (LMICs). RSV prevention has advanced substantially by the recent identification of the conformational structure of the major antigenic sites (prefusion F protein). There are two key development areas: vaccination of pregnant women and long-acting monoclonal antibodies (mAbs) given to infants.

The first trial in pregnant women used a nanoparticle vaccine to target the RSV prefusogenic F protein. Medically attended (MA) (39%) and hospitalized (44%) RSV-LRTI was reduced with no safety concerns, but the primary endpoint was not met (except in South Africa where >50% of participants were enrolled) (1). Two recent maternal vaccine trials targeted the RSV prefusion F-antigenic site. One was halted early when a safety signal identified an imbalance of preterm births. Mothers in LMICs receiving additional vaccines during a specific period of the trial experienced a reduction in the absolute risk but also experienced an increased relative risk of prematurity, leading to the imbalance (2, Abstract 126). A Phase 3 trial of the second vaccine reduced severe MA RSV-LRTI at 90 (81.8% efficacy) and 180 (69.4% efficacy) days of age, with 57% efficacy in reducing MA RSV LRTI at 90 days and no safety concerns (3); licensing is in progress.

Palivizumab, an expensive, short-acting RSV mAb is limited to use in high-risk infants in high income countries (HICs). Amino acid modification of the Fc region enabled the development of two longer acting mAbs given as a single intramuscular dose per season: nirsevimab (targeted to site 0) and clesrovimab (site IV) of the prefusion F protein. Nirsevimab in a Phase 3 study in preterm infants reduced MA RSV LRTI (70%) and hospitalized RSV-LRTI (78%) to 150 days postdose (4). In late preterm and healthy term infants, corresponding efficacy was 74.5% and 62.1%, respectively in a primary analysis where coronavirus disease [COVID-19] impact on RSV epidemiology resulted in too few hospital RSV-LRTI cases for adequate power (5). At full enrolment the study reported a reduction in hospitalized RSV-LRTI of 76.8%, with similar reduction in (76.4%) (6). Pharmacokinetic and clinical data indicate that single-dose nirsevimab should provide protection against RSV-LRTI for at least 5 months, with RSV-neutralizing antibodies remaining sevenfold higher than baseline at 361 days (4). Nirsevimab is now licensed in the European Union and the United Kingdom, and under U.S. Food and Drug Administration review. Clesrovimab is in Phase 3 (ClinicalTrials.gov ID NCT04767373) with promising Phase 1/2a results (2, Abstract 157).

There may also be benefits additional to preventing RSV-LRTI, with potential reductions in all-cause LRTI, antibiotic prescribing, otitis media, and subsequent wheezing illness. Reductions in all-cause LRTI and antibiotic prescribing were observed among infants of mothers receiving the RSV vaccine and in infants receiving nirsevimab (5, 7). The COVID-19 pandemic saw large reductions in childhood pneumococcal invasive disease, lobar consolidation, and LRTI, concomitant with the disappearance of RSV (8), which suggests that prevention of RSV-LRTI may lead to reductions in non–RSV-LRTI and severe invasive disease.

The decision to implement a maternal vaccine or mAb to protect infants depends on several factors. Vaccination of pregnant women may be more challenging, and the duration of protection may be shorter than for a mAb. Additionally, transplacental antibody transfer may be impaired by preterm birth or by maternal hypergammaglobulinemia (e.g., uncontrolled HIV disease or malaria). The success of mAb use in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) management has been tempered by genetic mutations, either rendering COVID-19 monoclonals ineffective or requiring larger doses to achieve a similar clinical benefit. Suptavumab, a promising Phase II RSV mAb, was recently rendered ineffective by genetic substitutions preceding its Phase III trial (9). Nirsevimab and clesrovimab, situated in highly conserved areas of prefusion F protein, are considered less susceptible to mutational change. It is important to note that RSV genome sequencing will be monitored by means of the World Health Organization RSV surveillance and online repository (www.gisaid.org).

A key consideration for global implementation is cost and affordability. HICs will consider the cost-benefit for population or high-risk (e.g., preterm or congenital heart disease) deployment in infants and whether to introduce a seasonal or year-round approach. In HICs, 1 in 56 healthy term infants are hospitalized with RSV in their first year, suggesting a significant potential impact (10). Children in LMICs experience the highest rates of RSV illness and mortality but have limited access to health care and high numbers of community-based RSV-related deaths. Inequality in vaccine access and immunization is complex but is largely driven by wealth disparities; addressing global inequity in child health requires equitable access to immunization. GAVI, the Vaccine Alliance historically supported access to vaccines in LICs, whereas tiered pricing may offer access in middle-income countries. Cost-benefit analyses indicate substantial value across healthcare settings, especially as both interventions are single dose. A global commitment to funding and implementation should remain a priority for RSV preventive interventions to ensure rapid and affordable availability in LMICs.

Although new preventive strategies could radically reduce RSV disease and LRTI globally, there may be potential unintended consequences. During the COVID-19 pandemic, there were dramatic reductions in the incidence and hospitalizations for pediatric RSV-LRTI. As RSV resurged after the COVID-19 lockdown, reports emerged that children who had missed their first-year exposure were at risk of disease in their second year. However, most severe disease and mortality occur in young infants; furthermore, a delayed risk was not observed in the second year of follow-up of children in the nirsevimab Phase 3 trial. Success in reducing RSV-LRTI may also leave an ecological niche that might, over time, become occupied by another virus by competitive adaptation. Continued global viral surveillance will be key in determining this risk.

An effective preventive strategy against RSV disease in infants has taken decades to develop. At least two products will be available soon, and several others are in late-stage development (e.g., www.path.org/resources/rsv-vaccine-and-mab-snapshot, accessed March 9, 2023). The COVID-19 pandemic has shown that rapid global upscaling and implementation of vaccination is possible, including in LMICs. Access and affordability in LMICs are essential, where the impact will be greatest given the severity, number of cases, and mortality. If this does not occur, health inequities will be exacerbated. Now is the time for a concerted global effort to urgently fund and deliver effective RSV prevention strategies to all infants, especially those in LMICs.