Neele Rave

Respiratory Syncytial Virus (RSV) is a common virus that causes respiratory infections, especially in young children and older adults. Annually, there are an estimated 33 million RSV-related respiratory infections worldwide, with 3.6 million hospitalizations and over 101,000 deaths. The vast majority of these occur in low- and middle-income countries (LMICs), where the high disease burden places significant pressure on healthcare systems. Until the start of this PhD project in 2022, palivizumab was the only approved preventive measure against RSV infections in infants. This monoclonal antibody binds to the RSV F-protein, thereby preventing the virus from entering body cells. Due to its high cost, the use of palivizumab was limited to children at high risk of severe illness in high-income countries. However, new developments have led to innovative immunization strategies that can significantly reduce the risk of severe RSV infections in early childhood. The World Health Organization (WHO) currently recommends two options: maternal PreF protein vaccination (RSVpreF, Abrysvo®, Pfizer) and a long-acting monoclonal antibody (mAb) for prophylaxis in infants (nirsevimab, Beyfortus®, AstraZeneca and Sanofi). The maternal vaccine is administered in the second or third trimester of pregnancy, so that the mother produces high levels of RSV-specific antibodies that are transferred via the placenta to the unborn child. This provides passive protection in the first six months of life, the period when infants are most vulnerable to severe RSV infections. Nirsevimab, on the other hand, is administered as a single intramuscular injection to infants before or at the start of their first RSV season, or immediately after birth if the child was born during the RSV season, and offers direct passive protection. In September 2025, the European Medicines Agency (EMA) also issued a positive opinion for another long-acting monoclonal antibody, clesrovimab (Enflonsia®, Merck), which is considered a promising additional option for RSV prevention in young children. In many high-income countries, a form of RSV immunization has now been introduced, ranging from exclusively maternal vaccination or nirsevimab to a combination of both strategies. In low-income countries, however, access to RSV prevention remains severely limited, meaning that the majority of the global RSV disease burden remains concentrated in these regions. After a general introduction to RSV and health economics, Part I of this dissertation focuses on seasonal patterns and clinical characteristics of RSV in the Netherlands, with special attention to the consequences of the COVID-19 pandemic. The pandemic had significant global consequences for respiratory infections. Measures such as physical distancing, school closures, and mask-wearing led to a drastic reduction in the transmission of many viral infections. In the winter of 2020–2021, RSV infections were virtually absent, followed by an unusual increase in the summer of 2021. Chapter 2 describes the disease burden of RSV in children under two years of age in the Netherlands, with a particular focus on changes in the typical winter pattern during and after the pandemic. Our analyses show that both the epidemiological and clinical characteristics of RSV have largely returned to the pre-pandemic pattern. Differences in age distribution and severity appear to be related to changes in social interactions and public health measures. As before the pandemic, severe RSV infections primarily occurred in children under six months of age after the pandemic as well. During my PhD research, RSV immunization was included in the Dutch National Immunization Program (NIP). Chapter 3 reflects on the implementation of this program and explores possibilities for further optimization. Since September 2025, all children born on or after April 1, 2025, are offered RSV immunization with the monoclonal antibody Nirsevimab in their first year of life, providing an important basis for protection. Analyses suggest that considering the birth month, as well as timely administration of the vaccination, are still relevant. A portion of infants already contract an RSV infection within the first 14 days of life, requiring hospitalization, and may fall outside the scope of the existing vaccination program. A more precise alignment of the immunization strategy with the birth month and timely administration could further increase the program's effectiveness. Part II shifts the focus to the impact of RSV infections on intensive care units (ICUs) in LMICs, where available data are often limited. In collaboration with ten study sites in LMICs, all children under two years of age, hospitalized with severe respiratory symptoms, were prospectively tested for RSV during two local RSV seasons. The results of this study, the RSV GOLD III–ICU Network Study, are described in Chapter 4. The multinational study showed that RSV accounts for a significant proportion of severe respiratory infections in young children. During the local RSV season, 29% of hospitalized children tested positive for RSV. Particularly noteworthy was that most life-threatening RSV infections occurred in children in the first six months of life, with almost half of the cases recorded in children younger than three months. This age distribution highlights both the increased vulnerability of young infants in these countries and the potential of available immunization strategies to prevent severe RSV infections in high-risk groups. Furthermore, this study formed the starting point of this dissertation and the basis for the selection of study sites for the RSV GOLD III–Health Economics Study, which later enabled the health economics studies in Part III. Chapters 5 and 6 focus on Cost-of-Illness (COI) studies for the RSV virus in Mozambique and Nepal. The studies provide insight into the costs of RSV infections in children under two years of age from the perspective of the healthcare system, households, and society. The analyses showed that Mozambique had the highest total costs for RSV infections in children under two years of age. The costs for life-threatening cases, characterized by ICU admissions, averaged 1161 USD, almost twice as high as the costs for severe cases (612 USD). Healthcare system costs were also high in Mozambique: 7 USD, 550 USD, and 928 USD respectively for non-severe, severe, and life-threatening cases. In Nepal, healthcare system costs for life-threatening and severe cases were only 58 USD. The data also show the significant financial burden on households. In Mozambique, household costs associated with RSV-related hospitalizations represented 43–145% of the monthly minimum wage, while in Nepal, household costs ranged from 168-400% of the monthly minimum wage. These studies provide valuable initial insights into the economic burden of RSV in LMICs and emphasize the importance of RSV immunization strategies to reduce both child mortality and poverty. Chapters 7 and 8 present cost-effectiveness analyses of new intervention strategies against RSV in Mozambique and Nepal. These analyses examined the introduction of maternal RSV vaccination (RSVPreF, Abrysvo®, Pfizer) and a long-acting monoclonal antibody (mAb) for infants (nirsevimab, Beyfortus®, AstraZeneca and Sanofi) over ten years (2025–2034). Each intervention was compared to the current situation where no preventive option is available. The primary outcome measure was the incremental cost per disability-adjusted life year (DALY) gained from the government's perspective. Our analyses show that both maternal vaccinations and mAbs can have a significant impact on reducing infant mortality and hospitalizations. Both interventions can be cost-effective provided the price is appropriate and potential support from Gavi, an organization that helps poor countries vaccinate children, is available. mAbs are expected to be more expensive than maternal vaccines, making future pricing information crucial for policy decisions. In Nepal, an RSV vaccine for pregnant women, at a price of US$5 per dose, could save an estimated 2,500 child lives (36%) and prevent 50,000 hospitalizations (25%) over ten years. A long-acting antibody for infants, on the other hand, could prevent slightly fewer deaths (over 2,000, 33%) but slightly more hospitalizations (over 53,500, 27%). In Mozambique, the same vaccine for pregnant women would cost approximately US$80 million and could prevent an estimated 4,700 deaths (43%) and 109,000 hospitalizations (32%). The long-acting antibody for infants would cost US$85 million and could prevent 5,000 deaths (47%) and 112,000 hospitalizations (33%). More than half of these costs could be recovered through healthcare savings. In short, both strategies can save many child lives and prevent hospitalizations. At a low price and with international support such as from Gavi, these strategies are affordable. By smartly aligning vaccination with the RSV season, the effect can be further increased. Chapter 9, the general discussion, addresses the role of health economic research in the implementation of RSV immunization strategies in LMICs. The chapter shows that health economics contributes to insights into the costs, benefits, and feasibility of new interventions. This information supports policymakers in prioritizing resources in settings with limited capacity. The chapter also emphasizes that this type of evidence is most valuable when collected at the country level, thus forming an important complement to epidemiological and clinical data on the disease burden and seasonal patterns of RSV. Although international guidelines and global models provide an important framework for decision-making, local epidemiological data, cost structures, and care practices can strongly influence the economic outcomes and feasibility of implementation. By combining context-specific data with international insights, health economic analyses can contribute to policies that are better aligned with local realities. At the same time, the discussion addresses that the translation of economic analyses into policy action in LMICs rarely proceeds linearly. Cost-effectiveness analyses are essential for prioritizing and justifying investments but cannot, by themselves, remove structural limitations such as competing health priorities and dependence on external funding. Health economic evidence should therefore be seen as a necessary, facilitating step that brings RSV immunization strategies closer to actual implementation. However, decisions remain dependent on financing possibilities, the readiness of the healthcare system, and sustained political and institutional willingness to translate scientific insights into action.