The session discussed the need for increased awareness and risk factors of RSV disease prevention, strategies and the characteristics of the infant population and to evaluate the implementation strategies for RSV disease prevention.

The introduction by Dr. Octavio Ramilo highlighted the background of Respiratory Syncytial Virus (RSV).and the need for treatment strategies. The session began with a polling question on the impact of COVID-19 on RSV seasonality, highlighting the need for flexibility in immunizing and protecting infants against RSV. Some other polling questions were the approximate proportion of infants hospitalized with RSV who are born healthy at term and have no underlying conditions, the belief that the implementation of an RSV disease prevention program needs to be a high priority. RSV has been occurring for a long time and pediatricians find it a challenge because of a virus protection against RSV. RSV has a global impact and there is a tremendous enhancement and investment in developing RSV preventive strategies. The PERCH which analysed the ideology of pneumonia, severe pneumonia in children hospitalised in low and middle-income countries has shown that viruses more frequently occur than bacteria and RSV has the highest incidence. (06:12). RSV is an RNA virus which is negative, it cannot be copied directly and has only 10 genes. The main antigens on the surface that induce antibodies and allow viral pathogenesis are the G protein that allows the virus to attach to the respiratory epithelium. Data from RSV circulation (NCH 2014-2021) has shown that every year there are around 2000 kids diagnosed with RSV. An interesting find from this circulation was that there were lesser cases of RSV during the pandemic but during the spread of the delta COVID-19 strain there was a surge of RSV cases (during summer) indicating that young infants experienced exposure to both viruses. The next increase in the number of RSV cases was seen during late fall and winter. From the past experiences of co-infections between RSV and other coronaviruses, there is a 15-20% incidence. A small percentage of co-infections were associated with increased disease severity. This makes the prevention of RSV critical and using COVID vaccines is important to protect children.

The first presentation by Dr. Joanne Wildenbeest focused on the strategies and considerations for the prevention of RSV disease. In order to develop strategies for prevention of a disease, the burden of disease is important. It is assumed that almost all children have an RSV infection by 2 years of age; around 10% of these children will get a lower respiratory tract infection and 1% will be hospitalised with RSV; < 0.1% need to be admitted to the paediatric intensive care unit. Infants who are born prematurely and children with congenital heart and lung disease have a higher risk of severe infection and hospitalisation and are treated with monoclonal antibodies. An accurate way of studying the incidence of RSV in healthy infants is through prospective vertical cohort. A study conducted in Europe on 9500 infants for respiratory tract infections and RSV infections or associated hospitalisations revealed that there was a 1.8% (1 in 56 infants) incidence of RSV-associated hospitalisation. The incidence of RSV acute respiratory infection overall was 26%; more than half of these children were seen by a doctor leading to an incidence of medically attended RSV incidence of 14%. Less than one per thousand infants were admitted to the paediatric intensive care unit; 80% of the admitted infants < 6 months of age. RSV can be prevented through pharmacological and non-pharmacological approaches. The pharmacological approach can be divided into 3 strategies-protection by monoclonal antibodies, extending the shelf-life of monoclonal antibodies, maternal immunisation where the mother gets vaccinated during pregnancy and antibodies are transferred to the placenta to the foetus and infant vaccination. The formulation of a RSV vaccine began in 1960 and a variety of vaccines and monoclonal antibodies are being developed and are currently in different phases. The main target for most vaccines is RSV Fusion protein, which enables fusion of the virus to the cell. The current landscape of RSV immunisation strategies include children, pregnant women, elderly, or those who are at risk for severe disease. The results of a phase 2b study (2020) in 1500 prematurely born infants treated with Nirsevimab or placebo showed a 70% reduction in medically attended RSV infections. The incidence of RSV-related hospitalisation was reduced by 78%. The study reported no adverse events or death which suggested that Nirsevimab has a favourable safety profile. A worldwide phase III study (MELODY) among 1500 infants randomised to Nirsevimab or placebo (2:1) showed an efficacy of 74.5% (relative reduction) for medically attended RSV at 50 days after injection. There was a 62.1% reduction in hospitalisation for RSV and safety profile was similar between the 2 groups. The post-hoc analysis for the full cohort of the study showed an efficacy of 76.4% against medically attended lower respiratory tract infection, 76.8% against RSV-related hospitalisation in healthy infants and 78.6% against very severe RSV, lower respiratory tract infection. A phase III maternal vaccination study (MATISSE study) was conducted where 7400 pregnant women were randomised (1:1) to receive RSV pre-subunit vaccine or placebo between gestational age of 24 and 36 weeks. The results of this interim analysis showed that maternal vaccination is effective against severe medically-attended RSV infection at 90 days with a vaccine efficacy of 81%. It was effective through 180 days after birth with a vaccine efficacy of 69%. The mechanism of maternal vaccination depends on transfer of maternal antibodies through the foetus. The transfer starts in the second trimester and increases during pregnancy, with also active transport of immunoglobulin G antibodies in the last trimester. This suggests that preterm-born infants have less maternal antibodies and it is currently not known whether preterm infants have sufficient protection by maternal vaccination In summary, RSV is a considerable burden and preventing RSV in all infants is essential. Monoclonal antibodies with a prolonged half-life can be a means of preventing RSV infections. It is important to consider whether to use one or a combination strategy, shared decision-making is necessary and inform future parents about the disease and prevention options.

The second presentation by Professor Paolo Bonnani discussed the considerations for implementation of an RSV disease prevention program. The important considerations for an effective strategy for protection against RSV by the World Health Organisation (WHO) states that there should be an indication and an immediate protection to prevent disease in early infancy. There should be no interference upon co-administration of other vaccines; the timing of immunisation should be in accordance with the timing of the RSV season. Regarding the value proposition, the measure of prevention should be affordable, cost-effective and price should not be a barrier to access. The target population (preterm, term infants, with chronic or congenital disease). The duration of protection should be for the entire RSV season and it should cover both RSV A and B. The preferred product characteristics by the WHO for maternal immunisation include safety, schedule, non-interference, efficacy and the target population. The WHO recommends comparable safety and reactogenicity to routine vaccines for use during pregnancy. The preferred schedule is a 1-dose regimen. The target population includes women in the second and third trimester of pregnancy. Non-interference includes favourable safety and immunologic non-interference upon administration of other vaccines recommended for use in pregnancy. Lastly, there should be> 70% efficacy against RSV-confirmed severe disease in the offspring from birth to at least 4 months of age. The WHO requirements for passive immunisation against RSV in infants include safety, efficacy, co-administration, schedule and target population. There should be comparable safety and reactogenicity to other vaccines recommended by WHO given at the same age. The efficacy should be at least 70% against RSV-confirmed severe disease for at least 4 months following administration. While co-administrating, there should be no interference with any current vaccines administered to the infant. There is a preference for a 1-dose regimen given during birth or during the first 6 months of life. The target population are all infants in the first six months of life. There are some considerations between maternal immunisation and immunisation with monoclonal antibodies. The potential for protection of infants during the first RSV season for maternal immunisation is in infants born just before or during the season; infants born outside their RSV season may not be protected for the entire period. Preterm infants may not be protected as they may be born before vaccination and there may be no immunity transfer. The duration of protection may vary depending on the concentration of the maternal antibodies transferred and on the decay kinetics. The immunisation with extended half-life monoclonal antibodies can be given to a broad infant population which includes late preterm, full term, more than 35 weeks of gestational age and healthy preterm. One injection protects for at least five months with a potential for protection for RSV A and B. The administration can be timed to coincide with the RSV season. The antibody peak at the administration of birth is very rapid. The consistent protection by gestational age depends on maternal factors such as the level of antibodies reached after immunisation or the transfer mother to the newborn through the placenta. The implementation considerations rely on maternal immunisation rates. Immunisation with standard half-life monoclonal antibodies offers consistent protection by gestational age, across the medical standard RSV, lower respiratory tract infection. The consideration about implementation is that this could be administered during routine medical appointments. Another important consideration is seasonality, where it is important to have a wide surveillance of seasonality in temperate climates and understand the best period to offer monoclonal antibodies. Nirsevimab is approved by the European Medicines Agency for the prevention of RSV lower respiratory tract disease in neonates and infants during their first RSV season. A position statement from the French Paediatric Society of Pulmonology and Allergy recommends the systematic prevention of RSV bronchiolitis in all infants under one year of age with Nirsevimab from the next epidemic season. The position statement of the Spanish Association of Pediatrics, the Committee on vaccines, recommends the administration of Nirsevimab to all newborns and infants aged <6 months, in addition to yearly administration, to children <2 years with underlying disease that increase the risk of severe RSV infection. In Italy, a detailed position statement recommends Nirsevimab for RSV bronchiolitis management. The key points of the Board of the Calendar for life and the Italian society of Neonatology recognised that all infants are at risk for severe disease because the main risk factors are age under 1 year and seasonality. There are new long-acting monoclonal antibodies being recently approved by the European Medicines Agency which represent a new, effective strategy for protecting all infants entering their first RSV season. The implementation of this tool is that if there is an infant born during the RSV season, they will be given passive immunisation during their stay in hospital before discharge. If they are not born during the RSV season, they should be immunised before the start of the RSV epidemic. In conclusion, long-acting monoclonal antibodies represent a potential strategy for protection against RSV disease in a broad infant population. In infants born before the RSV season, or depending on infant/mother factors, maternal infections or conditions, maternal immunisation may provide sufficient protection. The paediatric vaccines may require multiple doses and will be unable to provide full protection to infants < 6 months of age. The implementation strategies for Nirsevimab for the prevention of RSV disease in broad infant populations require integration between hospital and primary care.

The post-session discussion highlighted that the implementation of the out-of-season strategy is strongly dependent on the organisation of a country’s healthcare system. Each country should find a solution to implement immunisation based on their seasons. If a country lacks a good disease surveillance system, then it should rely on the data of the neighbouring countries.

European Society of Paediatric Infectious Diseases (ESPID) 2023, 08 - 12 May 2023, Lisbon