Burden of the disease

RSV is known to be a leading cause of hospitalization, bronchiolitis and pneumonia in young children and represents a substantial burden to the health-care systems worldwide . The estimated global cost related to RSV infections was over 4.8 billion euros in 2017 . In a large systemic analysis, it was estimated that there are 33 million lower respiratory tract infections, 3.6 million hospital admissions and 101 400 deaths associated to RSV globally each year in children younger than 5 years of age. This represents 2% of all deaths in this age group and most of these deaths occur in low to middle-income countries (LMIC) . The burden is also significant in high-income countries with RSV representing the first cause of hospitalization in children less than 1 year of age in the United States . In two American prospective studies, RSV hospitalization rates for children less than 6 months of age were estimated between 14.7 and 17 per 1000, with most of the hospitalized children being previously healthy . Although prematurity and other risk factors have been associated with higher hospitalization rates, term infants are also at risk of severe RSV infections. A prospective European study including five high-income countries showed that 1 in 56 healthy term infants requires hospitalization for RSV infection during their first year of life . Driven by the concerning epidemiologic data, the World Health Organization (WHO) has identified pediatric RSV vaccination as a priority since 2017 and suggested a roadmap to develop maternal and pediatric immunizations to prevent RSV infections in all young children, including those living in LMIC .

Viral characteristics

RSV is a single-stranded negative sense ribonucleic acid (RNA) virus from the pneumoviridae family and the orthopneumovirus genus . Despite not being able to reassort genome sequences, RSV is considered to have a mutable genome and has a total of 11 proteins . Its bilipid viral envelope has two main transmembrane surface glycoproteins responsible for inducing neutralizing antibodies: the F fusion protein and the G attachment protein . The G protein enables attachment of the virus to the airway’s ciliated cells and the F protein plays a role in the fusion of the virus to the cellular membranes. . Based on the virus’s antigenic variability in reaction to monoclonal antibodies, RSV has been divided into two main antigenic subtypes, A and B . Significant variability still exists within each subtype, more often in the attachment of the glycoprotein G . This antigen diversity contributes to the pathogenicity of RSV and represents a challenge to vaccine development. The F fusion protein is more comparable between strains and is therefore the preferred protein for immune therapy development . More specifically, the prefusion F protein conformation (preF) is the target structure as it was found to play a bigger role in antigenic immune response compared to its more stable post-fusion form . Along with antigenic diversity and high reinfection rates, the need to immunize infants early in life, when they have an immature immune system and circulating maternal antibodies, has been a significant challenge to RSV vaccine development throughout the years .

Brief history of RSV immunization

In the 1960s, the first vaccine trials against RSV were conducted with formalin inactivated virus. A cohort of infants from 0 to 6 months of age who had never been infected with RSV was vaccinated. Although the serum antibody response was initially encouraging, 80% of the vaccinated infants required hospitalization during an RSV outbreak and two of them died . This serious adverse event is referred to as a vaccine-associated enhanced respiratory disease and significantly hindered research progress for RSV vaccination for decades afterwards. New technologies in the 1980s led to a better understanding of the viral structure and more specifically to the identification of the F fusion surface glycoprotein as mentioned above . In the 1990s, multiple trials looked at passive immunization using intravenous immunoglobulins in at risk pediatric populations . The PREVENT study did so in premature infants with bronchopulmonary dysplasia and showed promising results with a reduction of 40% of RSV hospitalizations in the vaccinated group . However, because of its risk of fluid overload and its interference with the vaccination calendar, the product was quickly removed from the market. Efforts in research then shifted to more specific passive immunization methods with monoclonal antibodies (mAb) .

Monoclonal antibodies

Palivizumab is a humanized mAb targeting the F protein that was first approved in 1998 by the Food and Drug Administration of the United States . It is now used in multiple high-income countries to protect against severe RSV infections in high-risk populations. Indications may vary depending on the country, but targeted populations include premature infants with or without bronchopulmonary disease and infants with hemodynamically significant congenital heart disease . Many trials have shown the efficacy of palivizumab including a 2013 Cochrane meta-analysis which reported evidence of a statistically significant decrease in hospitalizations compared to the placebo group . Although the intramuscular route is more convenient than the intravenous immunoglobulins, palivizumab requires monthly injections during the RSV season to maintain active mAb in the circulation. This requires significant resources from both the families and healthcare teams, especially with the interseasonal activity of RSV during the COVID-19 pandemic.

A new mAb, nirsevimab, was market approved in the United Kingdom in November 2022 and more recently in North America to prevent RSV in neonates and infants. In contrast to pavilizumab, nirsevimab specifically targets the pre-F protein and has an extended half-life due to triple amino acid substitutions in the fragment crystallizable region of the protein. A single dose given prior to the RSV season covers for the full season . The MELODY trial showed protection in healthy term and preterm infants from medically attended RSV lower respiratory tract infections as well as associated hospital admissions and severe RSV after receiving one weight-based nirsevimab dose. Furthermore, fewer adverse events were reported in the nirsevimab group compared to the placebo group, suggesting no safety concerns . Other ongoing trials for nirsevimab include the phase 3 CHIMES (China, NCT05110261) and HARMONIE (France, the UK, Germany NCT05437510) trials currently recruiting healthy preterm and term infants . Furthermore, a third mAb with a similar structure to nirsevimab is currently in a phase 3 trial: clesrovimab (NCT04938830) recruiting 1000 children younger than 1 year of age in multiple countries worldwide.

Prefusion F vaccines for adults

Although there are currently no approved vaccines for active immunization of children against RSV, there are two newly approved vaccines for adults over the age of 60. Both vaccines are bivalent protein-based subunits of the stabilized pre-F protein from the two antigenic groups A and B. The vaccines have been approved in the United States, Europe, and Canada since 2023. Clinical trials have shown the efficacy of preventing symptomatic RSV-associated lower respiratory tract disease in adults <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='≥’>≥≥
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60 years of age . In the large ongoing phase 3 RENOIR trial with 34 284 participants, there was 2.38 cases of RSV per 1000 person-years in the vaccinated group compared to 6.30 cases per 1000 person-years in the placebo group with no safety concerns .

Maternal immunization

Maternal vaccination is an interesting option for prevention of RSV in infants, especially in those younger than 6 months. The goal is to increase the infant’s serum antibody concentration after birth by increasing transplacental antibody transfer. Studies have suggested that most of the maternal antibodies are transmitted to the fetus during the late second and third trimesters, therefore mostly targeting prevention in term infants . Efficient transplacental transfers of RSV antibodies have been documented, but it has been unclear if there is a correlation between the antibody concentration and the severity or onset of the disease . In addition, a phase 2b trial demonstrated safety of maternal pre-F protein-based vaccination as well as a good neutralizing antibody response in the infants . However, a 2020 clinical trial using a non-stabilized pre-F vaccine did not meet criteria for maternal vaccination efficacy on RSV-associated respiratory tract infections in infants within 90 days of birth . The recent MATISSE trial used the now approved stabilized pre-F vaccine and showed encouraging results for medically attended severe RSV-associated lower respiratory tract illnesses in infants with a vaccine efficacy of 81.8%; 99.5% CI, 40.6 to 96.3. In this trial, pregnant women were vaccinated with a single dose of the vaccine between 24 and 36 weeks of gestation. However, there was no statistically significant difference between the vaccine and placebo groups for medically attended RSV-associated lower respiratory tract infections .

Other ongoing pediatric trials

Multiple clinical trials are currently in the early phases (phase 1 and 2) for active immunization in children using live-attenuated, nucleic acid (mRNA) and recombinant vector vaccines . Live-attenuated vaccines use a form of the virus that has decreased pathogenicity but with a preserved replication function to create an adequate immune response in the host. These vaccines are mostly intranasal and are unlikely to provoke enhanced disease . Currently, there are multiple phase 1 (NCT04919109; NCT05281263; NCT03213405) and phase 2 (NCT04491877; NCT04909021; NCT03916185) ongoing clinical trials from sites worldwide for children over the age of 6 months. Despite some promising early-phase results from 5 vaccine candidates, no live-attenuated vaccine trials have progressed to phase 3 so far .

After the COVID-19 mRNA pediatric vaccines, one clinical trial is currently looking at an mRNA RSV vaccine in children ages 5 to 24 months (NCT05743881). The mRNA vaccine is also in phase 3 for the elderly and is suggesting good efficacy in that age group (NCT05127434) . Finally, one clinical trial is looking at a vector-based vaccine using adenovirus and pre-F. Vector-based vaccines use a carrier vector to present specific components of the virus. This vaccine had shown promising results in adults and previously RSV-infected children, but its phase 3 trial in adults has since been discontinued (NCT03303625) . A phase 2 trial has been started in RSV sero-negative toddlers from ages 12 to 24 months (NCT03606512).

Future directions for research

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  There are several ongoing RSV prevention trials for children and maternal immunization. A consensus for indications will be needed, although considering the potential burden of lost working days for caregivers, preventative strategies could be beneficial to all infants.

  
  
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  Further, as RSV is particularly devasting in low-middle income countries, access to such preventive strategies at reasonable cost with practical logistical delivery strategies will be particularly important.