The New Era for Respiratory Syncytial Virus Prevention for Infants in China: A Pediatricians’ Perspective

This year marks a new era for respiratory syncytial virus (RSV) prevention for infants in China, as it is the first time since the detection of RSV that we have an option, namely, the long-acting monoclonal antibody nirsevimab, to prevent the infection and associated disease burden. We highly support the recent Chinese expert consensus that recommends nirsevimab as a new strategy for preventing RSV infections among infants born before or during their first RSV season, whether or not they have risk conditions putting them at higher risk of severe RSV disease.[1] This article provides an overview of RSV, the associated disease burden, the newly approved monoclonal antibody (nirsevimab), the international position on and experience of this product, and the implications for RSV control in China. 1. RSV RSV is a common virus responsible for acute respiratory infections, which can lead to acute lower respiratory tract illnesses (LRTI) in infants, such as pneumonia and bronchiolitis.[1] RSV is highly contagious with a mean R0 of 4.5.[2] The epidemic peaks of RSV usually occur from November to April the following year in northern China, but seasonal peaks are less typical in southern China.[3,4] During/post the COVID-19 pandemic, the pattern of RSV circulation has been less clear, but a return to the regular seasonal pattern is expected soon. The yearly seasonal circulation and lack of effective control measures mean RSV infection is a potential public health concern. We have recently witnessed a “resurgence” of RSV in the USA, resulting in critical care on a larger scale during the COVID-19 pandemic.[5] In addition to the burden on the sick infants and their families, the winter outbreak can overwhelm hospital resources.[6] 2. Disease burden of RSV infection among infants in China RSV is responsible for an excessive disease burden in infants. After acquiring RSV infection, up to 40% of infants may develop bronchiolitis or pneumonia.[7] The impact of RSV infection in infancy may last several years.[1] Studies show that early-life RSV infection increases the risk of asthma or recurrent wheezing.[8,9] A China Centers for Disease Control and Prevention (CDC) surveillance study shows that RSV is the leading pathogen causing acute respiratory infections and community-acquired pneumonia in children aged 0–5 years, with detection rates of 14.59% and 18.28%, respectively.[10,11] China ranks among the countries with the highest incidence and hospitalization of RSV-LRTI in children globally. In 2019, there were 3.5 million cases of RSV-LRTI in Chinese children under 5 years old, accounting for over 10% of the global number, with 620,000 to 950,000 hospitalizations, approximately 17–26% of the global number, and China thus ranked second worldwide, following India.[12] Incidence data are currently limited in China. A 2019 study estimated that approximately 220,000 to 500,000 infants are hospitalized annually due to RSV-LRTI in China,[13] which corresponds to an incidence of 1,501–3,413 per 100,000 (the birth cohort in 2019 was 14.65 million[14]). Based on limited data on severe RSV disease in China, 10% of the 1,270 young children hospitalized for RSV-associated pneumonia during 2007–2015 in Beijing were admitted to pediatric intensive care units, and 21% required invasive (2.3%) or noninvasive ventilation (20.3%), but there were no deaths.[15] One small study (n = 46) reported a mortality of 5% among hospitalized neonates and infants with RSV-associated acute low respiratory tract infection.[16] A study from Zhengzhou city showed that approximately 85% of infants hospitalized due to RSV infection are healthy, full-term infants without underlying health conditions,[17] suggesting all infants are at risk of RSV infection. Some infants with serious underlying comorbidities are particularly vulnerable to severe RSV disease, even beyond their first RSV season, including preterm infants and those with chronic lung disease of prematurity or hemodynamically significant congenital heart disease.[1] RSV is also responsible for a substantial economic burden. The total economic burden was estimated to be US$1.7 million (in 2020 currency) for RSV-LRTI in Chinese infants (results based on China’s 2020 newborn cohort).[18] 3. Breakthrough in immunoprophylaxis of nirsevimab for prevention of RSV disease in infancy Nirsevimab is a long-acting intramuscular recombinant RSV F protein monoclonal antibody for the prevention of RSV disease in infants and young children at high risk of severe disease. It has been engineered with a triple amino acid substitution (YTE technology) to provide an extended duration of at least five months, which covers the length of a typical RSV season.[19] Nirsevimab is also shown to be effective at neutralizing both RSV A and RSV B subtypes because it binds to a highly conserved epitope in antigenic site Ø on the prefusion protein[19] The product has been shown to be effective at reducing LRTI caused by RSV in MELODY and HARMONIE studies, all published in the New England Journal of Medicine. For example, a placebo-controlled phase 2b trial[20] and the phase 3 MELODY trial[21,22] showed that nirsevimab was safe and effective against medically attended RSV-associated LRTI in healthy preterm and term infants in their first RSV season. The HARMONIE study, an ongoing phase 3b, randomized trial in conditions similar to those in routine clinical practice, aims to determine the efficacy and safety of nirsevimab as compared with standard care in infants who are not eligible to receive palivizumab.[23] To date, nirsevimab has demonstrated an efficacy of 79% against RSV medically attended LRTI (MELODY/Ph2b pooled data[24]) and 83% against hospitalizations (HARMONIE[23]). The safety and tolerability profile of nirsevimab has been found to be acceptable in infants.[19,20–23] The most frequent adverse reactions following nirsevimab administration in preterm and term infants were mild or moderate rash (0.7%), pyrexia (0.6%), and injection site reactions (0.4%).[19] The incidence of serious adverse events was not higher in the nirsevimab arm than in the placebo arm. No anaphylaxis or other serious hypersensitivity reactions were reported in the clinical trials.[20,21] To date, nirsevimab has been licensed in a number of countries or regions: the European Union (EU) and the UK in late 2022 and Canada, the USA, Australia, Brazil, Argentina, Chile, and China in 2023. In December 2023, the product was approved for use for the prevention of RSV-associated LRTI in neonates and infants born during or entering their first RSV season, as per the current indication in China, via priority review. This first-ever prophylactic monoclonal antibody has been approved for registration in the “Biological Product” category, representing a significant regulatory breakthrough in China. Previously and as per regulation, all the monoclonal antibodies in China were approved as “therapeutic biological products.”[25] The appropriate categorization of nirsevimab has paved the way toward protecting all susceptible infants. Nirsevimab has not been studied as a treatment in infants with RSV and is not licensed for the treatment of RSV infection. 4. Clinical considerations for administering nirsevimab in infants As per current indications in China (and the EU), nirsevimab should be administered from birth for infants born during the RSV season; for those born outside the season, nirsevimab should ideally be administered shortly before the RSV season begins. As in other countries, the seasonality of RSV in China varies geographically, which highlights the need to adapt immunization approaches to local contexts.[3] RSV seasonality is key to making recommendations about the timing of immunization against RSV. Two studies (from the USA and the EU, respectively) defined the RSV epidemic season onset as the first of two consecutive weeks when the weekly percentage of tests positive for RSV was ≥3% in eligible cases.[26,27] The recommended dose is 50 mg for infants with body weight <5 kg or 100 mg for those with body weight ≥5 kg. As a passive immunization option, nirsevimab is not expected to interfere with the active immune response to co-administered vaccines. Simultaneous administration of nirsevimab with age-appropriate vaccines is permissible.[28] Nirsevimab is administered intramuscularly, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection site because of the risk of damage to the sciatic nerve. As with any other intramuscular injections, nirsevimab should be given with caution to infants with thrombocytopenia or any coagulation disorder. Nirsevimab should not be administered to individuals with a history of hypersensitivity to the active substance or to any of the excipients in the product.[28] 5. International experiences of nirsevimab use In all countries where nirsevimab has been licensed for use, nirsevimab is indicated for the prevention of RSV in infants (including those who are term/pre-term, with or without underlying medical conditions, and born before/during the RSV season); currently, in the USA/Canada/Australia/Brazil/Argentina/Chile, the product is also indicated for children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. In the USA, nirsevimab is included in the U.S. CDC’s Child and Adolescent Immunization Schedule and also in the Vaccines for Children (VFC) program.[29] The VFC program helps provide immunizations at no cost to children whose parents or guardians may not be able to afford them, ensuring that all children have an equal chance of getting their recommended immunizations on schedule. The demand for nirsevimab has been much higher than anticipated despite an opportunistic supply plan built to outperform past pediatric immunization launches in the USA. A recent test-negative, case-control study showed an effectiveness estimate of 90% (95% CI = 75%–96%) of nirsevimab against RSV-associated hospitalization with a median time from receipt to symptom onset of 45 days (interquartile range = 19–76 days).[29] Nirsevimab is also provided free of charge to eligible infants in Spain (all regions), France, and Luxemburg. In a population-based real-world study from the Galicia region of Spain, in seasonally born infants and infants <6 months at the start of the immunization campaign, the effectiveness estimates of nirsevimab were 82.0% against RSV-related LRTI hospitalizations, 86.9% against severe RSV-related LRTI requiring oxygen, 69.2% against all-cause LRTI hospitalizations, and 66.2% against all-cause hospitalizations, respectively.[30] 6. Impacts of introducing nirsevimab and its implications for RSV control in China For individual infants, an effective prophylactic intervention against RSV infection can bring important health benefits. Hence, the use of nirsevimab has the potential to greatly reduce the proportion of RSV-associated LRTI cases as well as the associated long-term health impacts, such as impaired lung function, which are closely linked to recurrent wheezing, airway hyperresponsiveness, and asthma.[1] At the population level, the use of nirsevimab with good coverage is expected to reduce the public health and economic burden associated with RSV disease among infants. A recent modeling study assessed the impact of nirsevimab on RSV-LRTI events and associated costs for all infants in their first RSV season in China.[18] Assuming a coverage of 20% for preterm infants and 10% for term infants given nirsevimab, it is estimated that 78,597 RSV-LRTI cases (44,497 hospital admissions), 369 in-hospital deaths, and 12,260 quality-adjusted life year (QALY) losses would be averted, saving approximately US$131 million.[18] Greater coverage, namely, 60% for preterm infants and 30% for term infants, would lead to further decreases in the RSV-LRTI health and economic burden, preventing 235,791 RSV-LRTI cases (133,493 hospital admissions), 1,107 in-hospital deaths, and 36,780 QALY losses and saving US$393 million.[18] 7. Challenges to overcome in using nirsevimab to prevent RSV in infants in China The implementation of nirsevimab as RSV prevention for infants in China faces multifaceted challenges and requires strategic considerations. One prominent challenge lies in the low awareness of RSV and its health impact on young children among not only parents, but also primary healthcare providers. To address this issue, experts, especially pediatricians, must take a leading role in educational initiatives/events in collaboration with medical societies and public health partners, including industry. In addition, with the medical and preventive integration campaign being rolled out nationally, hospitals and community healthcare centers (CHCs) are critical elements in immunization services. Hospitals, for example, maternal and child health units, are the front lines of providing immunization for newborns and taking care of infants seeking medical care. On the other hand, to maximize the public health impact of nirsevimab, CHCs would be a suitable pathway to immunize previously healthy infants, especially given that most infants susceptible to RSV are otherwise healthy and born at term. A mindset shift is required, and passive immunization using prophylactic biologics also plays a key role in infectious disease prevention. Although nirsevimab is licensed, preventing a disease using a prophylactic biologic is a new concept for many healthcare professionals and parents, and close collaboration among health authorities, hospitals, and CHCs will be needed to integrate the concept of passive immunization in relevant public education. Furthermore, while the price of the product in China is currently not available, the price setting should consider how much most families can afford. More importantly, the benefits and importance of preventing RSV disease among infants should be effectively communicated to parents and healthcare practitioners. 8. Future view Maternal vaccination is an alternative or additional strategy to the use of nirsevimab for the passive immunization of young infants against RSV disease. Recently, an RSVpreF vaccine was approved in the USA and recommended in pregnant individuals at 32 through 36 weeks gestational age for the prevention of RSV-associated LRTI in infants from birth through 6 months of age.[31] Available data suggest that its use may be constrained by the timing of administration relative to RSV circulation and by conditions that could impact the transplacental transfer of antibodies from mother to infant, such as prematurity or immunocompromising conditions. Potential risk of preterm birth could also be a concern, and robust, post-marketing safety surveillance is required to assess any potential, new safety signal.[31] With the introduction of prophylactic options, we, as Chinese pediatricians, are navigating a transformative journey in RSV prevention for all infants.[1] By leveraging international experiences and tailoring our approach to address unique challenges in China, we are poised to usher in a new era in public health for children, ultimately fostering a brighter and healthier future. Future improvements in RSV infection control will require the highest quality data to be generated through robust studies.[1] Meanwhile, the development of new candidate vaccines and monoclonal antibodies also highlights the need for reliable surveillance of RSV. Funding This work is supported by the Shanghai municipal three-year action plan for strengthening the construction of the public health system (2023-2025) GWVI-2.1.2. Author Contributions Mei Zeng conceived the content of the article. Mei Zeng and Lisu Huang wrote the paper. Zhiming Chen critically reviewed the paper. All authors read and approved the final manuscript. Conflicts of Interest None.

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