Recommendations on Respiratory Syncytial Virus (RSV) Immunisation Strategies for Infants and Young Children in Countries with Year-Round RSV Activity

1. Introduction

Respiratory syncytial virus (RSV) infection is a major contributor to morbidity and mortality among young children. Globally, in 2019, 33 million cases of RSV-associated lower respiratory tract infection (LRTI) episodes were reported in children aged 0 to 60 months, with an estimated 3·6 million RSV-associated LRTI hospital admissions [1]. RSV infection accounted for 2% of all deaths in children aged 0 to 60 months; specifically, RSV infection contributes to 19% of RSV-related deaths within the first 6 months of life [1]. Notably, children in low-income and middle-income countries made up over 95% of RSV-related acute LRTIs and 97% of RSV-related deaths [1]. In the absence of effective therapy for RSV, prevention with monoclonal antibodies (mAbs) immunisation given to infants and maternal RSV prefusion F (RSVpreF) vaccination are proven interventions that could reduce case-related morbidity and mortality.

The advancement and real-world evidence on immunisation for RSV prevention necessitates local experts’ evaluation to inform its potential implementation within the Malaysian healthcare system. This position paper, developed by an expert panel of 12 members appointed by the College of Paediatrics, Academy Medicine of Malaysia, aims to provide recommendations on infant immunisation with long-acting mAbs and maternal vaccination against RSV in Malaysia. The expert panel includes key opinion leaders in paediatric respiratory medicine, neonatology, paediatric infectious disease and immunology, microbiology, as well as public health and bioethics. The recommendations were informed by literature search using PubMed and grey literature; cost-effectiveness analyses were incorporated where available.

2. Epidemiology of RSV in Malaysia

2.1. RSV as a Major Respiratory Pathogen in Children

Several Malaysian studies have demonstrated that RSV was among the most prevalent respiratory pathogens detected using respiratory samples [2,3,4,5]. In a 27-year retrospective study (1982–2008) of hospitalised children below 5 years in Kuala Lumpur, 26·4% of respiratory samples were tested positive by immunofluorescence or viral culture, of which 70·6% were RSV [2]. More recent studies from Peninsular Malaysia report similar RSV positivity rates of 15·9% (2015–2019, 23,000 cases tested via multiplex polymerase chain reaction [PCR]) [3], 17·1% (2017–2022, 4,084 samples tested via direct fluorescent antibody [DFA]) [4], and 14·3% (2017–2024, 45,884 samples tested via DFA) [6]. Meanwhile, in East Malaysia, RSV-A and RSV-B were detected from 19% and 8% of 438 nasopharyngeal samples using real-time reverse PCR or real-time reverse-transcription PCR, respectively, at Sibu and Kapit Hospitals, Sarawak over 12 months [5].

2.2. Age-Group Vulnerability

Younger children are more vulnerable to RSV infections, evidenced by a median age of 8 to 12 months reported across Malaysian studies [4,7,8,9]. Children under 2 years old are at the highest risk of RSV-related hospitalisation, with approximately 85% of admissions recorded for this age group [3,9]. Most of these children were previously healthy, with more than 80% of hospitalised children with no documented comorbidities [8]. Although a recent local study reported no RSV-related mortality over 3 months [8], a case fatality rate of 1·6% among Malaysian children below age 5 was observed in another study conducted from 2008 to 2013 [9].

2.3. Lack of Immunity Against RSV Virus and Disease

A Malaysian study reported a resurgence of RSV cases post-COVID-19 period, which increased sharply with a positivity rate of 36·3% in July-August 2022 following a sharp decline during the pandemic (8·3% in July-August 2020), surpassing pre-pandemic levels (20·6% during 2017–2019) [4]. This phenomenon is primarily attributed to immunity debt incurred during the COVID-19 period, described as decreased population immunity following an extended period of reduced exposure to circulating pathogens [10]. This raises concern as delayed RSV exposure may predispose children to more severe illness later in childhood [11], likely driven by immunological factors including: (i) lack of early-life mucosal priming [12], (ii) diminished secretory IgA and innate immune pattern recognition [13], (iii) waning of maternal antibodies in mothers who were not recently exposed to RSV [14], and (iv) the immaturity of the infant adaptive immune system at the time of first infection [15].

2.4. Seasonality of RSV Across Asia

Temperate countries such as China and Japan generally show well-defined peaks in the winter months [16], while non-temperate countries like Hong Kong [17], Taiwan [18], and Singapore [19] tend to experience less predictable outbreaks with residual RSV activity throughout the year. In Peninsular Malaysia, more pronounced infections peaks are observed either during the third quarter [3,20], or the end of the year [2,9,20,21,22]. As for East Malaysia, an earlier infection peak was observed in Sibu and Kapit, Sarawak from March to August [5]. RSV infection was independently associated with the rainy season in Kelantan (OR 3·31, 95% CI 1·44–3·69) [22]. A weak correlation between RSV infections and rain days was seen in epidemiological studies conducted in Kuala Lumpur [2,20,21]. While RSV patterns appear to vary across Malaysia, robust surveillance is warranted to better understand local transmission trends and guide effective prevention strategies.

3. Disease Burden of RSV

3.1. Impact on Resource Utilisation

RSV in younger children places a substantial strain on healthcare services, increasing demand for hospital beds and intensive care capacity. An average monthly bed occupancy of 115% in the paediatric ward was recorded at the Kuala Lumpur Women's and Children's Hospital, with RSV admissions accounting for 2–22% of total admissions; meeting inpatient demand would require 82 additional beds, at an estimated cost of RM188·6 million (RM2·3 million per bed) [23]. In the same facility, children with RSV infections also required critical care more often than those with non-RSV infections (23·1% vs. 15·4%, respectively), with a significantly longer median length of stay (4 days [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] vs. 3 days [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]) [24]. Across two local studies, the need for paediatric intensive care unit (PICU) admission ranged between 15–15·3%, non-invasive ventilation between 10·2–11·2%, and mechanical ventilation between 2·5–6·9% [8,9]. High RSV case volumes in younger children can overwhelm hospital services and limit PICU capacity, resulting in suboptimal care.

3.2. Healthcare and Societal Costs of RSV Admissions

Severe RSV illness and hospitalisation result in substantial expenditures. The median direct cost of admissions for children below 5 years with acute respiratory infection at a teaching hospital in Kuala Lumpur was estimated to be USD 756 for a median hospital stay of 4 days [25]. Despite government subsidies, the median direct out-of-pocket cost remained at USD 189, translating to 16·4% of monthly household income [25]. Lost parental productivity also adds to indirect costs, with each hospital admission associated with a median of three lost workdays, bringing the median societal cost to USD 871 [25]. Likely an underestimate of the current actual costs, a local audit conducted three decades ago, involving children under 2 years old hospitalised for RSV infection between 1995 and 1997, reported a median admission cost of USD 358 for general inpatient care and USD 4,114 for PICU care, with a median length of stay of 4 days [26,27]. These demands are significant financial burdens that could potentially overwhelm the government budget allocated for healthcare and as such, preventive strategies should be considered to ease healthcare resources utilisation.

3.3. High Risk Populations for Severe RSV Disease

A disproportionate burden of RSV infection is seen among at-risk patient populations. Preterm infants under 37 weeks gestational age (GA) accounted for 25% of RSV-LRTI hospitalisations; among infants below 6 months, admission rates is almost four-fold for below 32 weeks GA (RR 3·87) and two-fold for 32 to 37 weeks’ GA (RR 1·93) compared to all children below 2 years [28]. Local hospital admission data on RSV report a substantial proportion who were extremely preterm infants (26 to 28 weeks’ GA), with nearly half (45%) required PICU admission at the Kuala Lumpur Women's and Children's Hospital [29]. Meanwhile, the FLIP-2 Spanish prospective study involving hospitalised premature infants (32 to 35 weeks’ GA) reported that 17·8% were admitted to ICU and 7·4% required mechanical ventilation [30].

Infant risk stratification for RSV hospitalisation is a subject of interest, especially from an economic perspective in resource-limited settings, as it helps prioritise prophylaxis for those at highest risk of severe disease. The risk factors for severe RSV infection leading to hospitalisation are outlined in Box 1.

Box 1. Risk factors for severe RSV infection leading to hospitalisation

• Gestational ages ≤ 35 weeks [30,31]
• Congenital heart disease [28,31]
• Chronic lung disease and bronchopulmonary dysplasia [28,31,32]
• Congenital anomalies or syndromic infants (e.g., Down’s Syndrome) [28]
  Neuromuscular disorders [31,33]
• Immunodeficiency disorders [31,32]

Prior to the recommendation of universal immunisation against RSV for all infants, palivizumab prophylaxis for preterm infants below 35 weeks’ gestation was the primary preventive strategy in many countries [34]. In Malaysia, while the Paediatric Pharmacy Services Guideline advises administering palivizumab to infants with chronic lung disease or a history of prematurity (< 35 weeks’ GA) [35], the Universiti Kebangsaan Malaysia teaching hospital reserves palivizumab for preterm neonates < 29 weeks’ GA, weighing 1,000 g and below, and/or diagnosed with bronchopulmonary dysplasia [36]. Although some settings secured budget allocation for infants at the highest risk of RSV disease [36], most Malaysian public hospitals administer palivizumab on an ad hoc basis without specific funding, reflecting the absence of a coordinated national policy.

3.4. Long-Term Clinical Sequelae Following RSV Infection

In children, clinical manifestations of RSV infection can range from mild respiratory symptoms to severe illness with acute and long-term consequences. That said, non-medically attended mild RSV infections can also have persistent symptoms beyond 15 days in half (50·5%) of healthy, term infants in the form of rhinitis (99%), cough (96·9%), and wheezing (66%) [37]. This can result in substantial social burden among parents, seen as impairment in usual daily activities (in 59·8% of episodes), worries (75·3%), anxiety (34%), and work absenteeism (10·8%) [37]. In more serious cases, infants who experience RSV bronchiolitis within their first 6 months of life have around 30% higher odds of developing pneumonia and otitis media, as well as requiring antibiotics in the following 6 months [38]. Early-life RSV LRTI can have long-term respiratory sequelae, including recurrent wheezing [39], asthma [40], abnormal lung function [41], and post-infection bronchiolitis obliterans [42]. Overall, RSV infections can result in substantial morbidity, often requiring medical attention in the long-term.

4. The Virus, Mechanism of Disease and Immune Defences

RSV (Figure 1a) is a single-stranded RNA virus that belongs to the Orthopneumovirus genus of the Pneumoviridae family, with two major subtypes—RSV A and RSV B [43]. Upon inhalation, RSV first infects the airway epithelial cells in the upper respiratory tract, then spreads to the bronchioles in the lower respiratory tract, where viral replication becomes more effective [44]. For viral entry into the host cells, the attachment glycoprotein (G) binds to the cell surface, while the fusion glycoprotein (F) facilitates membrane fusion [43]. RSV F protein then inhibits interferon-λ production, leading to continuous viral infection that becomes amplified [45]. This is accompanied by airway damage largely driven by immune-mediated response [45]. If confined to the upper airways, RSV infection typically presents with symptoms of an upper respiratory infection; however, in previously unexposed infants, the virus often spreads to the lower respiratory tract, causing LRTI [44].

Younger children are more vulnerable to severe illnesses from airway obstruction due to their smaller airways, reduced respiratory capacity, and lower respiratory reserve [44]. Additionally, protection against RSV infection in infants relies on maternal antibody levels, which wane rapidly after birth and are mostly absent at 6 months old [46]. These children are also susceptible to RSV reinfections, demonstrating primary infection rate of 86% and reinfection rate of around 35% in their first 3 years of life [46]. RSV reinfections could be attributed to short-lived primary RSV infection-induced antibody response, compounded by the immune system’s limited ability to develop efficient protective immunity against the virus, a rapid decline of antibody levels, and antigenic variations of RSV strains in subsequent epidemic seasons [46].

Efforts to develop active immunisation against RSV in infants have so far been unsuccessful, with progress remaining slow [47]. This is largely due to concerns about formalin-inactivated vaccine causing enhanced respiratory disease and the limited suitability of live attenuated vaccines in immunologically immature infants [48]. Interference from maternal antibodies in the first 6 months may also neutralise vaccine antigens before eliciting a strong immune response in infants [47]. Nonetheless, ongoing trials, mostly involving live attenuated vaccines administered intranasally, offer hope for safe and effective infant RSV immunisation [47].

At present, protection against severe RSV infection in children relies on passive immunisation, using mAbs and maternal RSV vaccines that target different antigenic sites of the RSV prefusion and postfusion proteins (Figure 1b) [47]. The RSV F glycoprotein is highly conserved and refolds from a metastable prefusion form to a stable postfusion form during viral entry, therefore an ideal candidate for passive prophylaxis development [49]. Palivizumab is an mAb that targets site II of the RSV F protein to neutralise the virus [50]; nirsevimab binds to site Ø, blocking the conformational change required for viral entry into host cells [50]; clesrovimab targets site IV of the F protein [51]. Meanwhile, the maternal vaccine is a bivalent subunit formulation containing prefusion antigens derived from RSV A and RSV B [52].

5. Current RSV Immunisation Approaches

5.1. Passive Immunisation

In June 1998, palivizumab became the first mAb approved by the US FDA for the prevention of RSV in high-risk children [53]. Infants who meet the criteria for prophylaxis may receive up to five monthly doses of palivizumab during their first RSV season, and at the start of their second season if indicated [54]. This schedule is based on its half-life of 20 days [55], which confers an estimated protection period of 28 days per dose [56]. A 2021 Cochrane review determined that palivizumab prophylaxis significantly reduces RSV-related hospitalisation in high-risk children (RR 0·44, 95% CI 0·3–0·64) [57]. Nonetheless, its short duration of action, the need for repeated monthly doses, and its high cost, support the recommendation for targeted immunisation of high-risk infants to reduce severe disease in a cost-effective manner [58].

Nirsevimab, the first long-acting mAb, was introduced in July 2023 to prevent RSV-associated LRTI in infants during their first RSV season and in high-risk children up to 24 months during their second RSV season [59,60]. With a half-life of 71 days, nirsevimab provides almost immediate protection after a single dose, which lasts for at least 5 months [55]. Its efficacy has been established in multiple pivotal trials (Table 1) [61,62,63,64,65], with a meta-analysis of 45,238 infants reporting a pooled efficacy of 88·4% (95% CI 84·7–91·2) against RSV-related hospitalisation [66]. The MEDLEY trial found that nirsevimab has a safety profile comparable to palivizumab [67]; there is also some evidence that the RSV protection could linger for a bit longer, with post-hoc analysis reporting nearly ten-fold higher and more sustained RSV-neutralising antibody levels up to 1 year [55].

The availability of nirsevimab has marked a paradigm shift in RSV prevention from targeted immunisation of high-risk infants to universal immunisation of all infants [68]. The NIRSE-GAL study in Galicia, Spain achieved 92% coverage, demonstrating 70·7% (95% CI 42·4–85·1) effectiveness against RSV-related LRTI hospitalisation and 80·3% (54·6–91·5) effectiveness in preventing RSV-related LRTI hospitalisation requiring oxygen support during the 2023-2024 season, with no new safety signals identified [69]. Similarly, Chile’s NIRSE-CL study achieved a coverage of 94% nationwide, resulting in effectiveness of 76·4% (72·6–79·7) against RSV-related LRTI hospitalisation and 84·9% (79·5–88·9) against ICU admissions [70]. Meanwhile, the REVIVE study conducted in Western Australia reported an adjusted effectiveness of 88·2% (73·5–94·7) against RSV-associated acute respiratory infection hospitalisations over 7 months [71]. The consistent effectiveness observed across real-world studies highlights the public health value of universal infant immunisation with nirsevimab.

A new mAb, clesrovimab, has recently received approval in June 2025 for prevention of RSV LRTI in infants born during or entering their first RSV season [72]. Despite clesrovimab having a shorter half-life than nirsevimab (44 days vs. 71 days), durable protection was observed across the typical five-month RSV season [73,74]. In the phase 2b/3 CLEVER trial (MK-1654-004), clesrovimab reduced RSV LRTIs at 150 days post-dose in healthy pre-term and full-term infants at birth to 1 year (efficacy 60·4%, 95% CI 44·1–71·9); even greater efficacy was observed in preventing LRTI hospitalisations (84·2%, 66·6–92·6) [73,75]. Additionally, the phase 3 SMART trial (MK-1654-007) found that clesrovimab is well tolerated in infants at high risk for RSV disease, with similar safety profile and RSV disease incidence rates comparable to monthly palivizumab through 150 days [74].

5.2. Maternal Vaccination

The RSVpreF vaccine is indicated for active immunisation of pregnant women to prevent RSV-associated LRTI in infants under 6 months old [76,77,78]. Although the European Medicines Agency approved its use for 24 to 36 weeks’ gestational period as per the MATISSE trial [52,78], slightly higher rates of preterm birth among RSVpreF recipients, though not statistically significant, perhaps led the US FDA to limit its use to 32 to 36 weeks’ gestation period in view of this potential risk [79,80]. Geographical variation was evident, with the vaccinated groups reporting a higher relative risk of preterm birth in Argentina and South Africa (significant in South Africa) [81]. A single RSVpreF dose between 32 and 36 weeks’ gestation period was also implemented in Canada and Argentina [82,83], while the UK and Australia recommend administration from 28 to 36 weeks [84,85].

Real-world data from Argentina’s BERNI study showed that maternal RSVpreF vaccination was effective against RSV-related LRTI hospitalisation from birth to 3 months (78·6%, 95% CI 62·1–87·9), with protection sustained up to 6 months (71·3%, 53·3–82·3) [83]. A modelling study in Australia suggests that achieving 70% year-round coverage of maternal RSVpreF vaccination could reduce infant hospitalisation under 3 months by 60% [86]. In Malaysia, the 2024 Malaysian Maternal Immunisation Consensus Guidelines positions RSVpreF as a highly efficacious vaccine and recommends its administration between 32 and 36 weeks gestation period [87].

5.3. Passive Immunisation vs. Maternal Vaccination

Both infant mAb immunisation and maternal RSVpreF vaccination offers distinct benefits and limitations, though no direct comparative data currently exist on their effectiveness in preventing RSV-associated LRTI in infants. Dosage and administration of infant mAb and maternal RSVpreF are outlined in File S1. Immunisation with mAb provides protective antibodies directly to the infant, unaffected by the variability in maternal response and transplacental transfer [79].

While maternal vaccination may offer immediate protection at birth and could be less susceptible to F protein mutations, its effectiveness might be compromised if antibody production or placental transfer is suboptimal, especially in immunocompromised mothers or if the infant is born prematurely within 14 days of vaccination [79]. RSVpreF induces robust immune responses in pregnant women, resulting in high RSV-neutralising titres in their newborns [88]. However, there is currently insufficient evidence on how sustained the antibodies in subsequent pregnancies are and whether they protect the pregnant women themselves against RSV infections.

6. Cost-Effectiveness of RSV Immunisation Approaches

Evaluating the cost-effectiveness of RSV prevention strategies in both targeted and universal approaches is essential to inform policymaking and optimise implementation. Table 2 outlines cost-effectiveness analyses of RSV prevention strategies conducted across countries.

6.1. Cost-Effectiveness for RSV Prevention in Malaysia

To support the expert panel’s deliberation, the study group performed a focused cost-effectiveness analysis of RSV prevention strategies in the Malaysian healthcare context. A decision tree model was used to account for direct and indirect medical costs related to RSV hospitalisation and mortality.

Findings from the cost-effectiveness analysis indicates that nirsevimab immunisation in high-risk infants prior to hospital discharge is the most affordable and costs substantially less than palivizumab, at almost one-tenth of its price. Nirsevimab alone or in combination with maternal vaccination is cost-effective compared to palivizumab; dominant strategies that are more cost-effective than palivizumab include i) nirsevimab for high-risk infants, ii) maternal vaccination with complementary nirsevimab for infants unprotected by maternal vaccination, and iii) maternal vaccination with complementary nirsevimab plus extended nirsevimab dosing for high-risk infants at 6 and 12 months. Nirsevimab for high-risk infants achieved the highest spending-to-savings ratio at 1:1·62, followed by maternal vaccination with complementary nirsevimab plus extended nirsevimab dosing for high-risk infants at 1:1·28. Further details of the cost-effectiveness analysis are outlined in File S2.

7. Ethics, Equity and Feasibility of RSV Immunisation

Historically, palivizumab has been reserved for high-risk infants due to cost issues, thereby excluding those at moderate risk and perpetuating preventable inequities in protection. The advent of new long-acting mAbs and maternal RSV vaccines now marks a critical ethical inflection point [95]. The true ethical imperative is not merely offering cheaper protection, but the systemic commitment to a universal access model, thereby dismantling the inequitable risk-stratification paradigm entirely. Policy discussions must pivot from cost-containment relative to the “palivizumab era” to assessing the absolute programme affordability required for universal deployment, acknowledging that even reduced per-course costs translate into significant, politically challenging budgetary demands on national health systems.

The concurrent emergence of maternal and infant immunisation strategies also raises uncertainties to which is the ethically preferable option beyond cost—should protection be delivered directly to infants via long-acting mAbs or indirectly via maternal immunisation? Long-acting mAbs may add to an already crowded paediatric vaccination schedule, potentially affecting adherence and raising concerns about pain, distress, and trust in healthcare services. Conversely, maternal vaccination avoids invasive procedures for the child but shifts the decision to the pregnant individual, invoking considerations of her own pain and distress, alongside parental responsibility and individual autonomy.

While existing national cold chain infrastructure is cited as supportive, potential limitations in system capacity and distribution topology can hinder the implementation of RSV prevention strategies. Maternal vaccination necessitates expanding cold chain access into antenatal clinics, while infant mAb delivery demands sufficient storage and seamless integration into community paediatric clinics. The challenge of achieving supply chain resilience extends particularly to last-mile delivery and comprehensive product tracking, which must bridge the infrastructural and administrative gaps between state-managed systems (e.g., National Immunisation Programme) and the often-decentralised private healthcare market, a divide common across diverse healthcare settings in countries with year-round RSV activity.

Healthcare workers should also be adequately trained, not only in clinical areas such as efficacy, contraindications, and adverse events, but also in operational competencies, including workflow integration and patient counselling. Additionally, parental acceptance remains crucial; as hesitancy is rarely resolved by simple “education”, public engagement must move beyond basic information, proactively addressing the unique scepticism surrounding a novel biologic through transparent dialogue and acknowledging the socio-political and experiential roots of distrust. Clinical efficacy must be actively validated and matched by deliberate, strategic efforts to build and maintain robust public trust.

8. Final Considerations and Position Statements

RSV prevention strategies should consider feasibility, administrative capacity, and budget constraints (Figure 2). With these considerations in mind, the expert panel advises targeted immunisation with long-acting mAbs for high-risk infants prior to hospital discharge as the pragmatic first step in the implementation of a national childhood RSV protection programme; immunisation may be repeated during the second year of life for eligible at-risk infants.

Complementary nirsevimab refers to nirsevimab given to infants: i) when the mother was not administered RSV vaccine during pregnancy, ii) when maternal vaccination status is unknown, or iii) when the infant is born less than 14 days after maternal vaccination.

Subsequent scale up of the programme to universal administration to protect all infants warrants serious consideration when resources permit. This can be achieved either through maternal vaccination with complementary long-acting mAbs or universal use of long-acting mAbs for all infants. As maternal vaccination is substantially less costly than long-acting mAbs, it may be worthwhile to explore the implementation of maternal vaccination for all mothers, especially in resource-limited settings.

Although real-world evidence showed effectiveness of long-acting mAbs for RSV prophylaxis as a seasonal strategy [69,70], the absence of clear seasonality in Malaysia, however, is a key limitation that complicates the optimisation of immunisation schedule for maximum protection. Therefore, the expert panel recommends addressing the issue of unclear seasonality with a combined strategy of maternal vaccination to protect infants from birth through 6 months, followed by universal infant immunisation with long-acting mAbs at 6 months to provide seamless protection across the first year of life. This strategy avoids potential interference that may occur with coadministration of other childhood vaccinations given at birth. Taken together, this addresses the high burden of disease in early infancy and the continued RSV circulation observed year-round (with peak incidence between 8 and 12 months of age) in a country with unclear RSV seasonality.