Respiratory Syncytial Virus in Neonates and Infants: New Frontiers for Its Prevention

1. Introduction

Respiratory syncytial virus (RSV) belongs to the genus Orthopneumovirus within the family

Pneumoviridae [1]. RSV is the leading cause of lower respiratory tract infections (LRTI), and a major contributor to morbidity and mortality among children under 5 years of age. Around 90% of children contract RSV within the first two years of life, and up to 40% of these will develop LRTI during the initial infection. Early life RSV-bronchiolitis is related to an increased risk of developing asthma and recurrent wheezing later in childhood. Most infections occur during winter in temperate climates and during the rainy season in the tropics [6]. The median age of children who are infected is about 5 months (ranging from 2 to 9 months). Approximately 45% of hospital admissions and in-hospital deaths related to RSV-LRTI occur in children under 6 months, with RSV estimated to cause between 55,000 and 190,000 pediatric deaths globally [4,7]. A population-based cohort study in Ontario, demonstrated that RSV infection is slightly more common in male (51.3%) than females (48,7%) [8]. The primary risk factors of severe RSV-associated disease include prematurity, bronchopulmonary dysplasia (BPD), and hemodynamically significant congenital heart disease (CHD) [9]. However, most severe cases and disease burden occur in healthy full-term infants who are not eligible for vaccination [10]. A retrospective observational study by Barbati et al. showed that over 30% of patients with RSV had at least one risk factor, often prematurity, while nearly 70% had no underlying conditions.[6]

Annually, RSV is responsible for millions of hospitalizations[10], 500 000 emergency room visits, 1.5 million ambulatory visits and 50 000 hospitalizations in children <24 months of age [11]. Hospitalization due to RSV infection is typical of children under one year of age, especially in children under three months of life [6]. In the United States (US), a retrospective study estimated that between October 2015 and December 2019, RSV-related hospitalizations accounted for 9.3% of all infant hospitalizations, making it the most common cause of infant hospitalizations outside the birth period. Given the low testing rate for RSV, the diagnosis of bronchiolitis could add another 3.7% of hospitalization [11]. Additionally, viral bronchiolitis is a major cause of pediatric intensive care unit (PICU) admission. Between 2000 and 2019 there was a significant increase in the number of PICU admissions not matched by an increase in the proportion of children at high risk [12].

Intensive care support was strongly associated with younger ages, with over 80% of PICU admission occurring in children under one year old and more than 70% of cases in infants under three months [6].

The COVID-19 pandemic significantly influenced RSV epidemiology, with a marked reduction in RSV infection and a substantial decrease of the rate of children hospitalized due to public health measures, such as mask-wearing, social distancing, and school closure. In 2020, RSV-related hospitalizations dropped by 79.7% in high-income countries, 13.8% in upper-middle-income countries, and 42.3% in lower middle-income country, like Kenya. The rate of RSV-bronchiolitis started to rise again in 2021 when these measures were stopped [3,13]. RSV infections have a significant burden on healthcare systems as demonstrated by several studies. In 2009, the total cost for hospitalizations due to bronchiolitis in the US was close to two billion dollars. Although hospitalizations rates declined between 2000 and 2009, costs have increased due to greater use of intensive care for high-risk cases [10]. From 2004 to 2018, bronchiolitis hospitalization and mortality rates remained stable [8].

A systematic literature review has shown that in the US the costs for RSV infection are higher in full term infants compared to premature ones, with full-term infants representing 82% of RSV hospitalizations and 70% of associated costs, despite the higher per-episode cost for extremely premature infants [11]. Currently, there is no specific, effective treatment for RSV disease. Management of acute RSV bronchiolitis is primarily supportive, including fluid administration and oxygen therapy [3]. Due to the lack of effective treatments, reducing RSV morbidity relies on preventive measures, including environmental controls and immunoprophylaxis. Preventive measures could also have the potential to reduce significant healthcare costs [11]. The aim of this narrative review is to evaluate various prevention strategies against RSV from pregnancy to early infancy.

2. Methods

Systematic research on the principal databases (PubMed, Scopus and the Cochrane Library) was conducted from November 1993 until 30 June 2024. In addition to the above-mentioned workflow, further relevant data were drawn from the main national and supranational institutions (i.e., AIFA, FDA and EMA) concerning the anti-RSV monoclonal antibodies and RSV vaccination issue and extracted from the guidelines and position papers of specialized scientific journals. Systematic review, guidelines, recommendations for the prevention of RSV infection, or bronchiolitis, in newborns and infants, guidelines or recommendations related to the use of palivizumab and nirsevimab, and papers that outlined or reviewed guidelines or recommendations related to the role of vaccination against RSV during pregnancy were included in our analysis. Exclusion criteria included papers (1) not focused on RSV; (2) not focused on RSV prevention; (3) not English language; and (4) editorial or comment articles.

3. Primary Prevention

Viral infections are spread by horizontal transmission, via saliva droplets, and contaminated surfaces, making environmental prophylaxis important as first-line of preventive measures. Key preventive actions include disinfecting contaminated surfaces and objects, frequent handwashing and decontamination of hands using alcohol solutions by parents or caregivers and other household contacts, avoid exposure to secondhand smoke of tobacco. Additionally, encouraging exclusive breastfeeding for at least six months can reduce the risk of viral infection and the morbidity of respiratory infections [3].

4. Vertical Transmission of RSV

Pregnancy is characterized by a physiologic immunosuppressed state, making women more susceptible to respiratory pathogens such as influenza and RSV at any trimester of pregnancy. Respiratory illness during pregnancy can lead to more severe consequences for the mother and for the fetus compared to those without these infections [14,15]. Although studies suggest RSV infection during pregnancy is relatively rare, occurring in 2-9% of cases, it can be transmitted vertically to the fetus, potentially causing adverse perinatal outcomes. Typical maternal symptoms are fever that lasts about 2-3 days, rhinorrhea and sore throat. More rarely, wheezing and breathing difficulties occasionally required hospitalization [16]. Evidence support that RSV can reach systemic circulation, allowing it to pass from the maternal to the fetal airways [17]. Fonceca’s study using droplet digital PCR (ddPCR) found RSV genome in cord blood mononuclear cells in 57.7% of term infants born to healthy, indicating vertical transmission [17]. Furthermore, Bokum et al. demonstrated that RSV infects primary human placenta cells in vitro, showing a particular tropism for placental fibroblasts. Through Hofbauer cells (migratory fetal macrophages in the chorionic villi), RSV can spread to the fetal circulation and reach the lungs, where it can establish a long-term infection and stimulate proinflammatory Th1 cytokines, potentially leading to complications during pregnancy and negative fetal outcomes [19]. Manti et al. confirmed acute RSV seropositivity in cord blood in newborns from mothers with a history of respiratory illness occurring in the third trimester of pregnancy. Seropositivity against RSV is associated with respiratory problems including neonatal respiratory distress syndrome, transient tachypnea of the newborn, apnea, respiratory failure, and pneumonia. Conversely, RSV-seronegative newborns did not develop neonatal respiratory issues [20]. Piedimonte’s study also showed that RSV can cross the placenta, affecting fetal lung development and leading to abnormal airway innervation and heightened reactivity postnatally, particularly after reinfection with RSV [21].

5. Vaccine in Pregnancy

Maternal immunization during pregnancy has been recommended in many countries because it leads to protection in infants immediately after birth and during the first months of life. Vaccinations during pregnancy protect women and infants from morbidity and mortality and severe infectious disease, and are currently limited to tetanus, influenza, pertussis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [22].

In August 2023, the Food and Drug Administration (FDA) approved RSV prefusion F (RSVpreF) vaccine (Abrysvo, Pfizer Inc.) for pregnant individuals [23], a decision recently mirrored by the European Medicines Agency (EMA) [24]. This vaccine contains stabilized prefusion F glycoproteins from RSV A and RSV B. This new strategy aims to prevent RSV-associated lower respiratory tract disease and severe lower respiratory tract disease in infants aged <6 months. Administered between 24 and 36 weeks of gestation, this vaccine provides passive immunity to the newborn through transplacental antibody transfer. The efficacy, safety, and immunogenicity of RSVpreF in infants born to people vaccinated during pregnancy has been evaluated in a placebo-controlled phase III clinical trial (MATernal Immunization Study for Safety and Efficacy [MATISSE]) [25].

Another RSV vaccine candidate for use during pregnancy (RSVPreF3-Mat) was investigated in a phase III clinical trial led by Dieussaert et al. However, the trial was halted early due to safety concerns, as data indicated a higher risk of preterm birth in the vaccine group compared to the placebo group [26].

RSVpreF efficacy against severe acute LRTIs due to RSV was 81.8% (99.5% confidence interval [CI] 40.6–96.3) during the first 90 days of life and 69.4% (97.6% CI 44.3–84.1) over the first 6-month. For not severe RSV-related, medically attended acute lower respiratory infections, vaccine efficacy was 57.1% (99.5% CI, 14.7–79.8)in the first 90 days of life and 51.3% (97.6%, CI 29.4–66.8) over the 6-month [25] (Table 1 and Table 2).

Table 1. Medically Attended Severe RSV-Associated Lower Respiratory Tract Illness.

Time Interval	RSVpreF Vaccine (N=3495)	Placebo (N=3480)	Vaccine_Efficacy (99.5% or 97.58% CI)
90 Days after birth	6 (0.2)	33 (0.9)	81.8 (40.6–96.3)
120 Days after birth	12 (0.3)	46 (1.3)	73.9 (45.6–88.8)
150 Days after birth	16 (0.5)	55 (1.6)	70.9 (44.5–85.9)
180 Days after birth	19 (0.5)	62 (1.8)	69.4 (44.3–84.1)
Time Interval	RSVpreF Vaccine (N=3495)	Placebo (N=3480)	Vaccine_Efficacy (99.5% or 97.58% CI)
90 Days after birth	6 (0.2)	33 (0.9)	81.8 (40.6–96.3)
120 Days after birth	12 (0.3)	46 (1.3)	73.9 (45.6–88.8)
150 Days after birth	16 (0.5)	55 (1.6)	70.9 (44.5–85.9)
180 Days after birth	19 (0.5)	62 (1.8)	69.4 (44.3–84.1)

Table 1. Medically Attended Severe RSV-Associated Lower Respiratory Tract Illness.

Time Interval	RSVpreF Vaccine (N=3495)	Placebo (N=3480)	Vaccine_Efficacy (99.5% or 97.58% CI)
90 Days after birth	6 (0.2)	33 (0.9)	81.8 (40.6–96.3)
120 Days after birth	12 (0.3)	46 (1.3)	73.9 (45.6–88.8)
150 Days after birth	16 (0.5)	55 (1.6)	70.9 (44.5–85.9)
180 Days after birth	19 (0.5)	62 (1.8)	69.4 (44.3–84.1)
Time Interval	RSVpreF Vaccine (N=3495)	Placebo (N=3480)	Vaccine_Efficacy (99.5% or 97.58% CI)
90 Days after birth	6 (0.2)	33 (0.9)	81.8 (40.6–96.3)
120 Days after birth	12 (0.3)	46 (1.3)	73.9 (45.6–88.8)
150 Days after birth	16 (0.5)	55 (1.6)	70.9 (44.5–85.9)
180 Days after birth	19 (0.5)	62 (1.8)	69.4 (44.3–84.1)

Table 1. Medically Attended Severe RSV-Associated Lower Respiratory Tract Illness [25].

Time Interval	RSVpreF Vaccine (N=3495)	Placebo (N=3480)	Vaccine_Efficacy (99.5% or 97.58% CI)
90 Days after birth	24 (0.7)	56 (1.6)	57.1 (14.7–79.8)
120 Days after birth	35 (1.0)	81 (2.3)	56.8 (31.2–73.5)
150 Days after birth	47 (1.3)	99 (2.8)	52.5 (28.7–68.9)
180 Days after birth	57 (1.6)	117 (3.4)	51.3 (29.4–66.8)

Table 1. Medically Attended Severe RSV-Associated Lower Respiratory Tract Illness [25].

Time Interval	RSVpreF Vaccine (N=3495)	Placebo (N=3480)	Vaccine_Efficacy (99.5% or 97.58% CI)
90 Days after birth	24 (0.7)	56 (1.6)	57.1 (14.7–79.8)
120 Days after birth	35 (1.0)	81 (2.3)	56.8 (31.2–73.5)
150 Days after birth	47 (1.3)	99 (2.8)	52.5 (28.7–68.9)
180 Days after birth	57 (1.6)	117 (3.4)	51.3 (29.4–66.8)

Table 2. Medically Attended Not Severe RSV-Associated Lower Respiratory Tract Illness.

Time Interval	RSVpreF Vaccine (N=3495)	Placebo (N=3480)	Vaccine Efficacy (99.5% or 97.58% CI)
90 Days after birth	24 (0.7)	56 (1.6)	57.1 (14.7–79.8)
120 Days after birth	35 (1.0)	81 (2.3)	56.8 (31.2–73.5)
150 Days after birth	47 (1.3)	99 (2.8)	52.5 (28.7–68.9)
180 Days after birth	57 (1.6)	117 (3.4)	51.3 (29.4–66.8)

Table 2. Medically Attended Not Severe RSV-Associated Lower Respiratory Tract Illness.

Time Interval	RSVpreF Vaccine (N=3495)	Placebo (N=3480)	Vaccine Efficacy (99.5% or 97.58% CI)
90 Days after birth	24 (0.7)	56 (1.6)	57.1 (14.7–79.8)
120 Days after birth	35 (1.0)	81 (2.3)	56.8 (31.2–73.5)
150 Days after birth	47 (1.3)	99 (2.8)	52.5 (28.7–68.9)
180 Days after birth	57 (1.6)	117 (3.4)	51.3 (29.4–66.8)

Most RSVpreF vaccine adverse events were mild to moderate. The most common local and systemic adverse reactions were pain at the injection site, headache, muscle pain, and nausea. Particularly, injection-site pain was the most frequent local reaction, occurring more often in RSVpreF vaccine recipients (41%) compared to placebo recipients (10%).

Regarding systemic events, muscle pain and headache were reported more frequently among vaccine recipients (27% reported muscle pain compared to 17% in the placebo group; 31% reported headaches compared to 28% in the placebo group). Other systemic adverse events occurred at similar rates in both groups. There was no statistically significant difference in the incidence of serious adverse events, including preterm births and hypertensive disorders of pregnancy (such as preeclampsia), between the vaccine and placebo groups. Preeclampsia was observed in 1.8% of vaccine recipients and 1.4% of placebo recipients, while fetal distress syndrome was also reported. In the phase 3 trial conducted within the recommended dosing window (32–36 weeks’ gestation), preterm births occurred in 4.2% of infants born to vaccinated mothers, compared to 3.7% in the placebo group, with all preterm births occurring at or after 36 weeks’ gestation [25,27].

6. RSV Immunoprophylaxis

6.1. RSV-Specific Polyclonal Human Immunoglobulin (RSV-Ig)

The presence of different antigenic subgroups within RSV strains A and B, along with the poor immunological response in newborn, prevented the development of an effective vaccine. This challenge shifted research’s focus toward o passive immunoprophylaxis against RSV as a preventive approach. Two controlled trials, NIAID-trial and PRE-VENT-study demonstrated the efficacy of monthly administration during November-April of 750 mg/kg of RSV-specific polyclonal human immunoglobulin (RSV-IGEV) in reducing hospitalizations due to RSV infections in a three category of patients [28,29,30]:

a)

infants with DBP under 24 months of age at the start of the autumn season;

b)

preterm infants between 29- and 32-weeks of gestational age, under 6 months old;

c)

preterm infants born at or before 28 weeks of gestational age, under 12 months old.

RSV-IGEVs have a few limitations:

-

patients required monthly hospitalized for intravenous administration and be closely monitored for potential complications, such as the risk of pulmonary edema due to fluid overload and the risk of pathogen transmission.

-

Intravenous administration is contraindicated in cases of CHD due to the risk of cyanosis induced by increased blood viscosity.

-

RSV-IG may interfere with the immune response of live-attenuated vaccines (MPRV vaccine should be delayed until 9 months after the last administration) [31].

6.2. Palivizumab

The limitations of human immunoglobulins prophylaxis led to the development of anti-RSV monoclonal antibodies. Palivizumab was the first humanized, genetically engineered murine monoclonal antibody to be approved for the prevention of RSV infections. Specifically, it is a IgG1κ monoclonal antibody, composed of 95% human and 5% murine sequences, targeting an epitope on the antigenic site A of the RSV fusion protein. Palivizumab has potent neutralizing and fusion-inhibitory activity against both RSV subtypes, A and B[32].

The "Impact-RSV" study, a multicenter, randomized, placebo-controlled trial conducted in 1998, was one of the earliest studies on Palivizumab’s efficacy. This trial involved 1,502 high-risk children—preterm infants (<35 weeks) under six months old and children under 24 months with BPD requiring medical therapy. Of these, 1,002 received 15 mg/kg of Palivizumab intramuscularly every 30 days from November to March, while 500 received a placebo. The study demonstrated that Palivizumab reduced RSV-related hospitalizations by 55% and significantly lowered the number of hospital days, days requiring oxygen therapy, and intensive care unit admissions [32].

A 2021 Cochrane review of five studies involving 3,343 patients confirmed that Palivizumab prophylaxis reduces RSV-related hospitalizations by 56%, with minimal effects on mortality or adverse events. Palivizumab was also associated with fewer respiratory-related hospitalizations and significantly reduced RSV infections and wheezing days [33].

The Italian Medicines Agency (AIFA) guidelines a 15 mg/kg dose of Pavilizumab is recommended every 30 days, administered intramuscularly in the anterolateral portion of the thigh, starting before the RSV season (October-November), and ending in March-April. Italian guidelines suggest the administration of Palivizumab for [34]:

a)

Infants born at ≤ 35 weeks' gestation, who are < 6 months old at the start of the RSV season;

b)

Infants born at ≤ 29 weeks' gestation, who are < 12 months old at the start of the RSV season;

c)

Children with BPD who required medical treatment in the previous 6 months and who are < 2 years old at the beginning of the RSV season;

d)

Children born with hemodynamically significant congenital heart disease who are < 2 years old at the beginning of the RSV season;

e)

Additionally, immunoprophylaxis can be considered for infants with cystic fibrosis, Down Syndrome, congenital diaphragmatic hernia, neuromuscular diseases and immunodeficiency.

The main limitations of palivizumab prophylaxis are:

-

difficulty in defining the target population based on the drug's cost-benefit ratio in terms of reducing hospitalizations due to RSV;

-

short half-life of the drug with the need for monthly intramuscular administration during the critical season.

6.3. Nirsevimab

Limitations of Palivizumab as immunoprophylaxis against RSV infections led to the development of Nirsevimab, a new recombinant monoclonal antibody with a long half-life that for universal seasonal anti-RSV prophylaxis through a single intramuscular administration. Nirsevimab is a human recombinant IgG1K monoclonal antibody that binds to the two F1 and F2 subunits of the RSV fusion protein, preventing viral fusing with respiratory cells and the subsequent infection [3].

The EMA approved Nirsevimab in November 2022, based on findings from three pilot studies: the D5290C00003 study [35], the MELODY study [36] and the MEDLEY study [37]. D5290C00003, a multicenter randomized, double-blind, placebo-controlled study involved a total of 1,453 preterm infants (29 to <35 weeks) during their first season of RSV A single 50 mg dose of Nirsevimab reduced the relative risk of RSV-related medical care by 70.1%, hospitalizations by 78.4%, and severe infections by 87.5% within 150 days [35]. he MELODY study, a multicenter, phase III trial randomized a total of 1,490 late term and preterm infants (EG ≥35 weeks) to receive a single intramuscular dose of Nirsevimab (50 mg for infants <5 kg, 100 mg for ≥5 kg) or placebo [36]. It reduced RSV-related medical care by 74.5% and hospitalizations by 62.1% within 150 days [36]. Both studies excluded patients with BPD or CHD, who were eligible for Palivizumab [35,36]. The MEDLEY study compared Nirsevimab (single dose) and Palivizumab (monthly) in 925 high-risk infants, showing similar efficacy in preventing severe RSV infections: 0.6% incidence in the Nirsevimab group versus 1.0% in the Palivizumab group [37].

Following EMA approval, large-scale studies evaluated Nirsevimab as universal RSV prophylaxis extended to all newborns [38]. The HARMONIE study, conducted in the UK, France, and Germany, enrolled 8,058 children from August 2022 to February 2023, demonstrating an 83.2% reduction in RSV-related hospitalizations [38].

Regional programs have also shown success. Galicia, Spain, was one of the first regions in the world to undertake an immunization program with Nirsevimab as prophylaxis for RSV respiratory infections. Specifically, between 25 September 2023 and 31 March 2024, 3188 (95.4%) of the 3340 infants born during the epidemic season, 6220 (89.9%) of the 6919 infants < 6 months, and 348 (97%) of the 360 children between 6 and 24 months with risk factors for severe RSV infections received an intramuscular dose of Nirsevimab. Overall, 91.7% of the eligible patients were immunized and excellent results were achieved. A single dose of Nirsevimab led to an 86.9% reduction in severe RSV infections requiring oxygen therapy, a 69.2% decrease in RSV-related hospitalizations, and a 66.2% reduction in total hospitalizations for any cause in Galicia during this period. [39].

In Italy, Valle d'Aosta was the first region to offer universal prophylaxis with Nirsevimab to infants without risk factors, similar to other Europeancountries, during the 2023-2024 epidemic season. All children born from May 1, 2023, and residing in Valle d'Aosta were included, except those with risk factors who had already undergone prophylaxis with Palivizumab. Nirsevimab administration began on December 2023, with a single intramuscular dose (50 mg if weight < 5 kg, 100 mg if weight > 5 kg). Newborns received the dose directly in neonatology departments (86% adherence), while infants born between May 1 and December 19, 2023, were vaccinated through the Public Health and Hygiene Service, with an adherence rate of 65%. Overall adherence reached 69%; among infants who did not receive Nirsevimab, 8.3% were hospitalized with RSV bronchiolitis, whereas none of the vaccinated infants required hospitalization [40]. The promising outcomes in Valle d'Aosta highlight the potential for a national RSV prevention program in Italy, potentially expanding Nirsevimab immunization across the country in the upcoming RSV season [40].

7. Conclusions

RSV remains a significant public health challenge, particularly for infants and young children. While supportive care represents currently the primary treatment for RSV infections, advances in prophylactic options, including monoclonal antibodies like Palivizumab and Nirsevimab, provide promising strategies to reduce the incidence and severity of RSV-associated illnesses. Maternal immunization also offers a new preventative approach, delivering protection to infants during their most vulnerable early months. Despite these developments, further studies are essential to refine protocols for RSV prevention, assess long-term outcomes, and optimize access to these preventive measures, aiming to mitigate RSV's global impact.