Respiratory syncytial virus-related disease burden in young children

Abstract

Respiratory tract infection with respiratory syncytial virus (RSV) is a leading cause of hospitalisation in young children. In high-income countries RSV-related mortality is generally infrequent, but globally RSV is an important cause of pneumonia-related mortality in children younger than 5 years. There is no treatment for RSV infection except supportive care and no vaccine available to prevent RSV infection. Passive immunisation with palivizumab, a humanised monoclonal antibody, is the only form of RSV prevention currently available. However, due to its cost palivizumab is only indicated in certain high-risk infant populations from high-income countries. Several immunisation strategies are currently under development with maternal immunisation being in phase-3 of clinical development. Due to immaturity of the immune system in neonates, paediatric vaccination is not possible directly after birth but aimed at an age of approximately two to three months. Vaccination of pregnant women is therefore a promising alternative if the youngest infants are targeted to be protected. Three different aspects of the RSV disease burden in young children were studied in this thesis. Global RSV-related childhood mortality was the first aspect studied. Clinical characteristics including age at death of children with fatal RSV infection were unknown. Individual patient data of 358 children who had died with RSV in hospitals across the world were described. It was found that at least 28% of children with RSV-related in-hospital death have comorbidities. The presence of comorbidity influences the age distribution of RSV-related in-hospital death, especially in high-income countries. Most children in low-income and middle-income countries are younger than six months at the time of RSV-related in-hospital death. The second aspect consisted of the potential effect of maternal vaccination on life-threatening and fatal RSV infection during infancy. While in phase-3 of clinical development, the expected effect of maternal vaccination on RSV prevention was still unknown. A mathematical model was developed to describe different factors that influence maternal vaccine efficacy. By applying this mathematical model to data from three cohorts of patients it was predicted that maternal vaccination against RSV may substantially decrease the number of life-threatening RSV infections in infants. Children with comorbidities (based on age at life-threatening infection) or preterm birth are likely to benefit less from maternal vaccination against RSV than healthy term children. The third aspect comprised the causal relationship between RSV infection and asthma development. Single, assessor-blinded follow-up of the randomised, placebo-controlled MAKI trial showed that prevention of RSV infection in otherwise healthy late preterm infants reduces the risk of parent-reported asthma at age six years, which is mostly explained by differences in infrequent wheeze. RSV prevention does not affect parent-reported frequent wheeze, lung function or physician-diagnosed asthma at age six years. Altogether, this follow-up trial demonstrates that despite the association found between RSV infection and asthma in non-randomised studies, a causal relationship seems unlikely in otherwise healthy late preterm infants. However, the trial may have missed detection of smaller, but clinically relevant effects of RSV prevention on different asthma phenotypes as a result of sample size. In summary, this thesis describes global RSV-related mortality, the potential of maternal vaccination and the relationship between RSV infection and asthma development.