Introduction

Respiratory syncytial virus (RSV) is a major worldwide public health challenge, particularly impacting children in low- and lower-middle-income countries (LMICs). Studies, such as the RSV GOLD, ICU Network, reveal that nearly 29% of children under two admitted to pediatric intensive care units (PICUs) in ten Gavi-supported LMICs tested positive for RSV, with 5% succumbing to the infection [1,2]. Data from the Pneumonia Etiology Research for Child Health study and the Child Health and Mortality Prevention Surveillance study shows that RSV significantly contributes to both pneumonia and infant mortality, making it a major cause of severe respiratory illness in young children [1]. The Global Burden of Disease study attributes one in every 50 deaths among children under five to RSV [3]. Around 20% of infants develop wheezing related to RSV within their first year, and 2% to 3% need hospitalization for the condition [4,5,6]. Estimates indicate that RSV leads to the hospitalization of over 120,000 infants annually in the United States, with the illness causing more than 200 deaths each year [7,8]. These results accentuate the need for comprehensive RSV surveillance and equitable access to preventive interventions, as 97% of RSV-related deaths occur in LMICs, where healthcare resources and access to advanced treatments remain limited [9]. Maternal immunization is an established public-health strategy (e.g., influenza and pertussis vaccination during pregnancy), demonstrating feasibility of antenatal delivery platforms and the principle of protecting young infants via transplacental IgG–mediated passive immunity. In addition to maternal vaccination, long-acting monoclonal antibodies for infants represent a complementary RSV prevention approach, particularly when antenatal access or optimal gestational timing cannot be achieved. Developing reliable measure of outcome for a variety of target populations and the challenges of clinical trials constitute two of the numerous barriers to the development of successful RSV therapies [10]. RSV is perceived as an extremely restricted and fragmented market, which may deter major pharmaceutical investment and impede regulatory routes intended to expedite the licensing of new pharmaceuticals. At the same time, the substantial public health burden of RSV prevents it from being classified as an orphan or neglected disease [11]. Therapeutic alternatives have remained sparse despite improvements in point-of-care diagnostics, RSV epidemiology, and the discovery of antiviral drug candidates. Rapid diagnostic improvements, while advancing point-of-care testing, risk losing valuable data without significant reporting mechanisms to track community-level infections [12]. Comprehensive knowledge of disease mechanisms and extensive clinical trials of novel treatments are necessary for future advancement. Additionally, RSV’s ability to suppress or evade B cell memory complicates vaccine development, raising questions about the feasibility of creating vaccines that elicit durable immunity [13,14]. Enhancing antiviral activity and lowering the likelihood of resistance development may also require combining inhibitors with various modes of action. These issues underscore the need for continued innovation and well-designed clinical trials to address the gaps in RSV prophylactic and therapeutic interventions.

Palivizumab (Synagis) is a monoclonal antibody developed to prevent severe RSV infection. It provides protection against both the A and B virus subtypes by targeting the RSV F-protein, which hinders the virus from fusing with host cells and preventing cell to cell spread [15]. Palivizumab, like all currently available passive or active immunization strategies, does not confer sterilizing immunity and does not completely prevent RSV infection; rather, its benefit lies in reducing disease severity and hospitalization risk [16]. Factors such as insufficient serum concentrations and delays in the injection schedule contribute to these shortcomings. Additionally, adherence to the injection regimen is often challenging, with compliance issues exacerbated by the lack of parental education and logistical barriers [17]. Despite improved compliance through home-based administration, this approach remains costly and difficult to implement on a wide scale [18]. Additionally, palivizumab’s application is limited as it lacks a license to treat established RSV disease [19]. Its potential for reducing the worldwide burden of RSV is hindered by its steep cost, which prevents it from being accessible in resource-poor nations where the bulk of RSV-related deaths occur [18]., however, have evolved substantially beyond palivizumab. Newer long-acting monoclonal antibodies (mAbs), such as nirsevimab and clesrovimab, have been engineered with extended half-lives, allowing protection with a single dose per RSV season [108, 109]. These agents have demonstrated high efficacy in preventing medically attended RSV lower respiratory tract infection and RSV-associated hospitalization in both term and preterm infants. Unlike maternal immunization, long-acting mAbs provide direct, immediate protection to the infant and do not rely on placental antibody transfer or maternal vaccine timing. As such, they are particularly well suited for infants born very preterm, infants with medical comorbidities, and those who may not optimally benefit from maternal immunization due to impaired transplacental antibody transfer or birth outside the optimal vaccination window. Maternal immunization serves a fundamental role in preventing disease in infants, and its use is not a novel concept. Vaccinations against influenza and pertussis during pregnancy are regularly advised in several nations to protect neonates through the transfer of antibodies [20]. In accordance with the passive antibody transfer principle observed in maternal influenza and pertussis vaccination, maternal RSV immunization is a compelling approach of protecting children at their extremely vulnerable hour, prior to their ability to receive vaccine or generate adequate autologous antibodies. Antibodies are transferred to the fetus through the placenta, with maternal IgG serving as the primary antibody subtype [21]. Maternal RSV vaccines offer important population-level advantages, including integration into existing antenatal care platforms and potential scalability in (low- and middle-income countries) LMICs; however, protection is time-limited by antibody waning and may be reduced in preterm infants or those born long after maternal vaccination. Mathematical modeling suggests that maternal RSV immunization can substantially reduce RSV-related hospitalizations in early infancy, particularly within the first three months of life [22]. The U.S. Food and Drug Administration (FDA) authorized Abrysvo, a groundbreaking novel vaccine designed to combat Respiratory Syncytial Virus (RSV), on August 21, 2023 [23,24]. This approval, which acknowledges Abrysvo as a promising preventative strategy against Lower Respiratory Tract Infections (LRTI) resulting from RSV in newborns throughout the critical phase spanning from birth to first six months of life, represents a significant milestone in maternal and infant health [25]. This advancement offers substantial promise in protecting vulnerable infants from severe complications associated with RSV-related LRTI. Abrysvo is a distinctive injectable bivalent prefusion F (preF) protein–based RSV vaccine designed to be administered as a single dose during late pregnancy, commonly between 32 and 36 weeks’ gestation [26]. Rather than using a live-attenuated or inactivated whole RSV virus, it contains stabilized preF antigens that are engineered to elicit robust RSV-neutralizing antibody responses. Following maternal immunization, vaccine-induced IgG antibodies are actively transported across the placenta—particularly in the third trimester—resulting in higher cord blood antibody concentrations and providing infants with passive protection during the early months of life when RSV-associated lower respiratory tract disease risk is highest [27]. This antigen-focused design, combined with optimized timing for transplacental antibody transfer, supports Abrysvo’s potential to reduce RSV-related morbidity in young infants, while emphasizing the importance of programmatic feasibility and antenatal care access to achieve maximal population impact. This review uniquely integrates maternal RSV vaccination and long-acting monoclonal antibodies within a unified passive immunization framework, critically examining their complementary roles, limitations, and implementation relevance for high-risk infants.

Review methodology

This structured narrative review evaluated the clinical efficacy, immunological mechanisms, safety, and public health implications of maternal RSV immunization, with emphasis on licensed and late-stage maternal vaccine candidates, including Abrysvo. Peer-reviewed literature was searched in PubMed/MEDLINE, Scopus, and Web of Science using Medical Subject Headings (MeSH) and free-text terms such as “Respiratory Syncytial Virus,” “maternal immunization,” “RSV vaccine,” “prefusion F,” “transplacental antibody transfer,” and “lower respiratory tract infection,” combined with Boolean operators (AND/OR). Inclusion criteria comprised English-language publications (2010–2024) reporting original data relevant to maternal RSV vaccination in pregnancy and infant outcomes, including clinical efficacy/effectiveness, immunogenicity and placental antibody transfer, pregnancy and infant safety outcomes, and implementation feasibility. Exclusion criteria included editorials, commentaries, conference abstracts, and secondary reviews without original data, as well as studies not involving pregnant populations or not reporting infant-relevant outcomes. Evidence was prioritized by clinical and policy relevance: (i) phase II/III trials and prespecified infant endpoints (medically attended RSV LRTI, hospitalization, severe disease); (ii) regulatory and technical documents and post-authorization safety monitoring reports to contextualize indications, gestational timing, and safety signals; and (iii) modelling studies, particularly those estimating potential impact in LMICs. Given heterogeneity in study designs, endpoints, and follow-up durations, findings were synthesized descriptively (without meta-analysis). Key clinical, immunological, and public health findings were summarized in tables and figures to enhance transparency and interpretability. The study selection process is summarized in Fig. 1.

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Study selection flowchart

Global burden and challenges of RSV in infants: a brief overview

The prevalence of respiratory syncytial virus (RSV)-associated LRTI is highest in low- and middle-income countries (LMICs), and the burden of RSV infection is unequally distributed worldwide (Fig. 2) [1,2]. An estimated 33 million RSV LRTI episodes occurred globally in 2019, leading to 3.6 million hospitalizations and 118,200 fatalities among children younger than five years. Among infants, those under six months of age bear the highest disease burden, accounting for 20% of all RSV infections and nearly 40% of RSV hospitalizations. A more recent 2019 analysis estimated 2.5–4.1 million RSV-related hospitalizations globally. However, most studies on RSV burden have been facility-based, limiting data on community deaths due to challenges in detecting RSV postmortem [28]. Additionally, over half of RSV-related in-hospital deaths occur in infants less than six months. Of these hospitalizations, 61% occur within the first three months of life, emphasizing the vulnerability of this age group to severe disease [29,30,31]. As illustrated in Fig. 1, the global burden of RSV is disproportionately concentrated in low- and middle-income countries, underscoring the urgent need for equitable access to preventive strategies. Further, one-fourth of all RSV LRTI hospitalizations are for preterm infants (born before 37 weeks of gestation), with early preterm infants (born before 32 weeks gestation) having twice the likelihood of needing hospitalization compared to late preterm infants. Approximately 93% of RSV cases, 92% of hospitalizations, and 89% of in-hospital mortality in preterm newborns occur in LMICs, accounting for the majority of these cases [32]. Hospitalizations for RSV LRTI in children under five years old declined substantially in high-income countries (HICs) throughout the COVID-19 pandemic, with hospitalization rates in HICs and upper-middle-income countries falling by about 80% [33]. However, by 2022, rates began to rise again in these regions, although they remained lower in LMICs [34]. This data underscores the significant healthcare disparities between high-income and low-income regions, with the latter facing challenges in providing adequate medical care and access to healthcare services [34,35].

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Global Burden of RSV Map. RSV Hospitalization and Mortality Rates. Darker shades indicate higher disease burden, predominantly observed in LMICs

Besides the high disease burden, RSV-associated mortality is particularly severe in LMICs, where over 97% of RSV-related deaths occur [3]. A significant portion of these deaths happen outside of the hospital, often due to a lack of awareness regarding the severity of RSV, with parents in these regions frequently unaware of the risks associated with the infection. RSV was responsible for nearly 41,000 fatalities in children under five and 10.7 million LRTI episodes in 2016 [36]. The total number of RSV-attributable deaths, including those occurring outside the hospital, could be as high as 101,400 [37]. Indeed, insufficient knowledge and delayed medical care may be responsible for up to 20% of RSV-related out-of-hospital mortality in LMICs [29,30,31]. Non-hospitalization rates for severe RSV LRTI are also disproportionately higher in LMICs. For example, studies from South Africa and Kenya has shown that hospitalization rates are comparable in South Africa but three times higher in Kenya for non-hospitalization rates, which occur when children experience severe illnesses but choose not to seek medical care [38,39]. Despite the apparent decrease in RSV hospitalizations in the early pandemic years, the burden of RSV remains substantial in LMICs. It particularly difficult to precisely estimate the number of RSV-related deaths resulting from underreporting, incorrect diagnoses, and considering that many of these deaths take place in community settings rather than hospitals [33]. Even though neonatal deaths from RSV are not as common as those in older children, neonates represent about 20% of RSV-attributable fatalities in the initial six months. This, however, is likely an underestimation due to the nonspecific clinical presentation of RSV in neonates [40]. RSV was identified to be causally linked to 6% of death from pneumonia episodes in Bangladesh and sub-Saharan Africa, according to studies from the Child Health and Mortality Prevention Surveillance (CHAMPS) Network. However, many of these deaths occur in the community, making data collecting a lot more difficult [1,2]. Consequently, RSV death estimates should be viewed as minimal numbers; the true burden may be far greater, especially in LMICs with limited medical services and surveillance. RSV has a substantial influence on critical care services; for instance, a large multicenter study conducted in 2024 found that 30% of children addressed to pediatric intensive care units (PICUs) in LMICs eligible for Gavi had RSV [41]. Despite its significance, limitations such as seasonal sampling, lack of co-infection testing, and disproportionate representation from Nepal (60% of cases) reduce the generalizability of the RSV GOLD—ICU findings [28]. Surveillance initiatives like eSARI provide fundamental data to track RSV seasonality and assess new preventive interventions [42]. Preventive measures like vaccination and better access to healthcare are of paramount importance in communities with limited resources, as preterm newborns are considerably more susceptible for severe illness and hospitalization.

Mechanisms of maternal RSV immunization

Maternal immunization provides early-life passive protection primarily by inducing RSV-specific neutralizing IgG that is actively transported across the placenta (FcRn-mediated) (Table 1) [43].

Placental IgG transfer increases with gestation and is most efficient in late pregnancy, resulting in high infant antibody levels at birth and protection during early infancy, when RSV risk is greatest [44,45,46]. As illustrated in Fig. 3, maternal RSV vaccination activates innate and adaptive immune pathways that culminate in RSV-specific antibody production and subsequent fetal exposure via transplacental transfer.

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Mechanism of antibody-mediated infant protection after maternal RSV vaccination. Maternal RSV vaccination induces innate and adaptive immune responses, promoting placental transfer of RSV-specific IgG to the fetus and resulting in early-life protection against RSV infection. Abbreviations: IgG; immunoglobulin G; RSV; respiratory syncytial virus

As the sole antibody type that can pass through the placenta, IgG protects the fetus against a range of pathogens [47]. The transfer of maternal antibodies offers significant passive protection, particularly in the initial months, before the infant begins receiving vaccinations or generating their own immune responses. The efficiency of placental antibody transfer increases as pregnancy progresses, ensuring that infants are born with a significant level of maternal immunity that helps guard against infections such as influenza, pertussis, and RSV, which can be particularly dangerous during the early stages of life [47]. In addition to placental transfer, breast milk provides an additional layer of immune protection. The primary antibody found in breast milk is IgA, which plays a fundamental role in mucosal immunity, particularly in the gastrointestinal and respiratory tracts. While IgA in breast milk helps provide some ongoing protection against respiratory infections after birth, it is the transplacental IgG that offers more direct and significant immunity to the infant before birth [48]. Additionally, studies reveal that IgG for some pulmonary infections, such COVID-19, can be identified in breast milk, however this is less frequent for other pathogens [47]. As demonstrated by the effectiveness of the influenza and pertussis vaccines, maternal vaccination has long been used to lower the risk of neonatal infections. Considering pertussis, vaccinations in the latter stages of pregnancy (ranging from 27 to 36 weeks gestation) considerably lowers the probability of neonatal pertussis, with up to 95% of neonatal fatalities during their initial few months being successfully prevented [49]. This protective effect is caused by the high quantities of IgG passed through the placenta, which can neutralize the pertussis toxin and offer immunity to the infant till they grow sufficiently mature to acquire their own vaccines [47,50]. A similar strategy is used for RSV immunization. The development of maternal RSV vaccinations attempts to equip infants with passive immunity by triggering the formation of RSV-specific IgG antibodies in the mother, which are then transferred across the placenta [51,52]. Reports have indicated that maternal RSV immunization can considerably lower the rates of RSV-related hospitalizations in newborns, particularly in the initial three months after birth, when maternal IgG levels are at their highest level [22]. An investigation reported a 44% decrease in RSV-related hospitalizations within the initial 90 days following birth utilizing a nanoparticle vaccine called ResVax, composed of the F protein of RSV [53]. However, this protective effect diminishes over time, and by the age of six months, the reduction in hospitalizations becomes minimal, as the infant’s immune system begins to develop its own response and the protective maternal antibodies wane. Mathematical models have demonstrated that maternal RSV immunization could lower hospitalization rates for RSV by as much as 6–37% in neonates younger than three months, with benefits being most prominent in the first few months after birth [22]. These models also show that the benefit of maternal vaccination decreases over time, with a smaller effect observed in children aged three to five months, and minimal impact after six months. Although the findings are promising, the models were based on data from high-income nations, within which hospitalization and fatality rates associated to RSV are lower than in low- and middle-income nations, indicating that regional differences may exist in the advantages of maternal vaccination. Despite the challenges in achieving sustained immunity, the principle of maternal vaccination, utilizing the strategy of transplacental antibody transfer, remains a promising technique for avoiding neonatal and infant morbidity and mortality from RSV and other infectious diseases [54,55]. Ongoing research and clinical trials of RSV vaccines, including those using the pre-F protein to enhance neutralizing antibody responses, hold promise for further improving the protection conferred by maternal immunization [56,57]. One of the critical lessons from earlier experimental RSV vaccine trials, such as those conducted in the 1960s, was the potential risk of enhanced respiratory disease (ERD), primarily mediated by Th2 cells, especially with inactivated RSV vaccines [58,59]. Despite this, maternal immunization with even less effective vaccines, such as formalin-inactivated RSV (FI-RSV), still provided passive protection to offspring, with no significant increase in immunopathology following RSV challenge. This suggests that maternal antibodies can offer substantial protection even when the vaccine itself might pose risks of Th2-mediated immune responses [60,61]. Unlike monoclonal antibodies (mAbs) like palivizumab, which require monthly injections and are limited to high-risk infants, maternal immunization could provide broader coverage without the need for repeated doses [62,63]. Additionally, the infrastructure for maternal vaccines already exists, as seen with influenza and pertussis vaccination programs, potentially enabling smoother implementation. However, challenges remain, including vaccine acceptance among pregnant women, which could affect uptake [46]. While maternal immunization offers indirect protection to the infant, long-acting mAbs provide direct, consistent protection for all infants, lasting at least five months and covering a typical RSV season [64]. Long-acting mAbs can be administered flexibly, offering protection even for infants born outside the RSV season, without relying on the infant’s immune system to mature [65,66,67]. Nevertheless, maternal immunization holds unique advantages, as it not only provides protection for the infant but could potentially offer some benefit to the mother as well, reducing her risk of RSV-associated complications during pregnancy [68, 69]. Both approaches—maternal immunization and long-acting mAbs—play complementary roles in RSV prevention. While mAbs may serve as an effective universal strategy, maternal immunization aligns with existing antenatal care practices, making it a key component in reducing the global RSV burden. Successful implementation will require addressing acceptance barriers, educating stakeholders, and integrating maternal vaccines into routine prenatal care to maximize their impact. Table 1 summarizes key mechanisms of maternal antibody transfer . The overall mechanism of maternal RSV immunization and transplacental antibody transfer is illustrated in Fig. 4 .

Table 1 Mechanisms of maternal RSV immunization and their protective effects in infants
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Fig. 4
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Dual Pathways of Infant Protection Induced by Maternal RSV Vaccination. This figure illustrates the immunological mechanisms through which maternal RSV vaccination protects infants both before and after birth. Intramuscular administration of the RSV prefusion F protein vaccine during pregnancy activates maternal antigen-presenting cells (APCs), leading to a CD4⁺ T cell-mediated immune response and the differentiation of plasma cells that produce RSV-specific IgG antibodies. These antibodies cross the placenta, providing passive systemic protection to the fetus, particularly in the lungs. After birth, maternal secretory IgA delivered through breast milk contributes to mucosal immunity in the infant’s respiratory and gastrointestinal tracts. Additionally, monoclonal antibodies may be administered directly to infants as an independent passive protection strategy. Abbreviations: APC, antigen-presenting cell; CD4⁺, cluster of differentiation 4; IgG, immunoglobulin G; IgA, immunoglobulin A; RSV, respiratory syncytial virus

Clinical efficacy of maternal RSV immunization in protecting newborns

Maternal RSV immunization offers a promising strategy to protect newborns by transferring antibodies across the placenta. Several vaccines have been tested for their clinical efficacy in averting severe RSV infections in infants (Table 2, Fig. 5). Comparing the safety and efficacy of various vaccines is fundamental in determining the best effective way to protecting vulnerable newborns.To strengthen cross-platform comparison and reduce repetition, vaccine performance is summarized comparatively across platforms (protein-based preF; nanoparticle; mRNA) and implementation considerations relevant to LMICs are highlighted throughout. Protein-based preF vaccines have the most advanced pregnancy efficacy evidence; nanoparticle vaccines provide supportive but more modest efficacy signals; and mRNA candidates are promising but remain under pregnancy evaluation. In LMICs, expected real-world impact will depend on antenatal coverage, gestational timing feasibility, cold-chain/cost constraints, and local RSV seasonality.

Abrysvo

Abrysvo, approved by the FDA for administration between 32 and 36 weeks of gestation, is administered as a single 0.5 mL intramuscular dose to protect infants from RSV-associated LRTI [70]. The vaccine’s clinical development included rigorous phase 1, phase 2, and phase 3 trials to assess its safety, immunogenicity, and efficacy. Initial phase I/II trials (NCT03529773, registered May 22, 2018) demonstrated significant increases in neutralizing antibody titers, particularly in participants with low baseline immunity. Although decreasing over a year, antibody levels were 4–5 times higher than baseline, indicating immunization in late pregnancy [71]. The trials also confirmed that RSV vaccination did not adversely affect coadministered influenza vaccine responses, although influenza vaccine responsiveness decreased in young adults [72]. A non-inferiority trial assessing the coadministration of RSV and tetanus, diphtheria, and acellular pertussis (Tdap) vaccines was conducted among healthy nonpregnant women in a phase IIb research (NCT04071158). While antibody-induced immunity met non-inferiority criteria for most pathogens, immunogenicity against pertussis was lower compared to single Tdap administration. This underscores the potential of maternal vaccination for multiple pathogens [73]. Another phase IIb trial (NCT04032093) vaccinated pregnant women (24–36 gestational weeks) with two dose formulations, one adjuvanted and one not. Interim 6-month data showed significant maternal antibody production and transfer to infants, significantly reducing infant RSV disease. The unadjuvanted formulation yielded higher infant antibody levels, unaffected by gestational age. Adverse events, including preterm deliveries, were comparable between vaccine and placebo groups, with a 3.7% preterm birth rate overall. The majority of congenital defects were modest and had no correlation with vaccination. Updated data, however, showed that the active group had a greater preterm birth rate (5.3%) than the placebo group (2.6%) [74]. Furthermore, a phase IIa RSV challenge study (NCT04785612) in younger individuals, including not pregnant participants, demonstrated significant protection towards RSV infection [75].

The MATISSE phase III trial (NCT04424316), a randomized, double-blind study, enrolled pregnant women between weeks 24 and 36 of low-risk, uncomplicated pregnancies from 18 countries. This trial demonstrated that Abrysvo significantly decreased the incidence of RSV- linked medically attended severe LRTI in infants. According to interim results, the vaccine efficacy within the first 90 days after birth was 81.8% for severe LRTI. However, the efficacy against RSV-associated LRTI (not severe) was 57.1%, falling short of the statistical success criterion. Protection against severe LRTI within 180 days postpartum was 69.4%. The trial also extensively monitored maternal and infant safety endpoints up to 12 months postpartum. There were no notable safety concerns, and the rate of serious adverse events was comparable across the vaccination and placebo groups. Adverse pregnancy outcomes were comparable, including preeclampsia (1.8% in vaccination recipients vs. 1.4% in placebo) and fetal distress syndrome (1.8% in vaccine vs. 1.4% in placebo). The vaccination group had a slightly greater preterm birth rate (5.7%) than the placebo group (4.7%) [26]. Another phase III trial (NCT05096208) examined the safety and immunogenicity of three distinct vaccination batches, confirming their consistency. The study reaffirmed the favorable safety profile and reactogenicity across vaccine lots [76]. The MORISOT trial (NCT06325657) is a phase III research that recently began to evaluate the efficacy and safety of Abrysvo in pregnant women having stable HIV infection. Eligible participants were in between weeks 24 and 36 of pregnancy. This trial aims to provide data on vaccine performance in immunocompromised populations, extending the applicability of maternal immunization strategies [77,78]. The FDA requires ongoing safety monitoring through systems like the Vaccine Adverse Event Reporting System (VAERS), directed by the CDC and FDA. VAERS data since January 2023 to April 2024 reported 199 serious adverse events, including premature labor (28 cases), cesarean deliveries (8), and preterm premature rupture of membranes (6). Of the premature labor cases, 21 were reported in women aged 30–39 years. Although the VAERS data align with clinical trial findings, such as the incidence of preterm births (5.7% in the vaccine group vs. 4.7% in the placebo group), it lacks the ability to establish definitive causal links due to its reliance on passive reporting. This limitation necessitates careful interpretation and further investigation. Ongoing Phase 4 studies and systematic reviews are essential to confirm the vaccine’s safety, refine its risk profile, and ensure the benefits of preventing RSV-associated illness significantly outweigh any potential risks [26].

RSV MAT

Targeting precisely the same prefusion F protein as Abrysvo, GSK plc’s maternal RSV vaccine candidate, RSV MAT, has undergone several clinical studies. NCT03674177, the first-in-human phase I study, evaluated immunogenicity and safety in non-pregnant women. It showed a favorable safety profile and supported further investigation during pregnancy [79].

In the phase II trial (NCT04126213), pregnant women (28–33 weeks gestation) received the vaccine, showing a comparable safety profile to the placebo group. Adverse events, including preterm labor and congenital anomalies, occurred at similar rates between groups, though a slight increase in hypertension and preeclampsia cases was noted but remained within general population levels. Both vaccinated women and the newborns showed elevated RSV-specific antibody titers [80]. Another phase II trial (NCT04138056) evaluated coadministration with Diphtheria-Tetanus-Pertussis (DTaP) vaccines in non-pregnant women. Although no significant interference in RSV immunogenicity was detected, mild interference was observed in DTaP responses, particularly for pertussis, with unknown clinical implications [81]. A large-scale phase III investigation, the GRACE trial (NCT04605159) assessed the vaccine’s efficacy and safety in preventing infants from developing lower respiratory tract disease (LRTD) caused by RSV. While efficacy was satisfactory, the trial was prematurely halted due to safety concerns, notably a higher preterm birth rate (6.8% in vaccinated vs. 4.9% in placebo groups) [82]. These findings led to the discontinuation of other trials, including NCT04980391 (high-risk pregnancies) and NCT05229068 (re-vaccination trial) [83,84]. A smaller phase III trial (NCT05169905) in non-pregnant females enrolled only nine participants before being terminated. However, another ongoing phase III trial (NCT05045144) continues to assess different vaccine lots and coadministration with influenza vaccines in non-pregnant women. To address safety concerns, GSK initiated a phase IIIb open-label trial (NCT05705440) for long-term follow-up of participants from previous studies [85,86,87]. GSK previously developed another maternal RSV vaccine candidate, GSK3003891A, which was abandoned due to formulation instability. The development of RSV MAT highlights the complexities of balancing efficacy and safety, particularly in vulnerable populations like pregnant women [88].

ResVax

Novavax, Inc. developed ResVax, a nanoparticle vaccine that encodes the RSV F protein. Its clinical development spanned multiple phases. Initiated in 2011, the Phase I Trial (NCT01290419) evaluated the vaccine in young male and female participants. The vaccine demonstrated an acceptable safety profile, with no toxicity observed and a marked increase in RSV-specific antibody titers, supporting progression to phase II trials [89].

Two trials were carried out to enhance the vaccine’s dosage and ascertain the effects of adding an adjuvant (NCT01704365, NCT01960686). There were fewer RSV infections after vaccinations, and enrolled women between the ages of 18 and 35 reported no serious safety issues. These results led to the selection of a mid-level adjuvant dosage in conjunction with a high antigen dose for maternal immunization trials [90,91]. Pregnant women in their third trimester were recruited for another phase II study (NCT02247726), which followed up with the infants for a year. Without raising any safety concerns, the vaccination showed protection against severe RSV infections in both women and infants. A significant amount of newborn antibodies with an average half-life of 40 days were found by cord blood analysis [92]. Participants in the major phase III study (NCT02624947) included pregnant women between weeks 28 and 36 of pregnancy. With similar rates of low birth weight, preterm delivery, and intrauterine growth restriction across the vaccination and placebo groups, no significant safety concerns were observed. The vaccine, however, failed to fulfill the established effectiveness threshold for medically serious lower respiratory tract infections (LRTIs) unique to RSV. Efficacy against RSV LRTI was 39.4% up to 3 months of age, and it increased to 58.8% for severe illness with hypoxemia. Remarkably, comparable effectiveness rates were seen for hospitalizations and all-cause LRTI. Although the study lacked statistical power to assess effectiveness on a country-specific basis, data also indicated greater protection against hospitalizations and severe cases in LMICs [93]. Despite promising data, ResVax is no longer part of Novavax’s development pipeline.

mRNA-1345

Moderna Inc. developed mRNA-1345, an mRNA-based RSV vaccine that targets the RSV F protein and is delivered effectively via lipid nanoparticles. In the NCT04528719 Phase I study, women and other healthy young individuals underwent vaccination. The results demonstrated a favorable safety profile, with elevated RSV-specific antibody titers observed within six months post-vaccination. These promising outcomes supported the vaccine’s potential for maternal immunization [94]. Pregnant women between the ages of 28 and 36 weeks are being recruited for the phase II study (NCT06143046). With follow-up scheduled for both mother participants and their infants, the investigation intends to assess the vaccine’s safety, immunogenicity, and effectiveness [95].

V-306

Virometix AG’s vaccine candidate V-306 targets the RSV F protein’s FsIIm epitope. The vaccine failed to provide the expected neutralizing or IgG-specific immunity in the phase I study (NCT04519073). Consequently, it could be necessary to modify the formulation of V-306 in order to attain the intended immunogenic response [96].

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Comparative overview of maternal vaccines under development against respiratory syncytial virus (RSV). This figure illustrates the current status of five maternal vaccine candidates designed for administration during pregnancy to protect newborns against lower respiratory tract infections (LRTIs) caused by RSV. Each area displays the technological platform, regulatory status, available data on clinical efficacy and immunogenicity, relevant safety signals (particularly preterm birth), and the estimated feasibility of implementation in low- and middle-income countries (LMICs). Included are vaccines based on protein subunits (Abrysvo and RSV MAT), nanoparticles (ResVax), mRNA (mRNA-1345), and synthetic peptides (V-306). Color-coded icons indicate key features such as reported efficacy (), development halted due to safety (), lack of clinical data (❔), and visual classification of LMIC viability ( ◍ high, ◍ moderate, ◍ low). The central illustration emphasizes the maternal-fetal focus of this preventive strategy. Information is based on completed or ongoing clinical trials as detailed in the main text

Table 2 Summary of clinical efficacy and safety of maternal RSV vaccine candidates
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Public health implications and policy considerations for RSV maternal immunization

Broader health implications of RSV maternal immunization

The broader health implications of RSV maternal immunization extend beyond reducing infant mortality. By averting a significant number of RSV-related hospitalizations and deaths, particularly in LMICs, maternal vaccines can alleviate the burden on healthcare systems, reduce economic costs associated with infant care, and improve long-term health outcomes for vulnerable populations [97]. Additionally, the widespread implementation of maternal immunization programs can enhance global health equity by prioritizing regions with limited access to healthcare and high RSV mortality rates. These efforts also highlight the importance of strengthening antenatal care services, ensuring optimal vaccine timing during pregnancy, and addressing barriers such as vaccine accessibility and public awareness. The potential success of RSV maternal immunization serves as a model for other maternal vaccine initiatives, underscoring the critical role of maternal health interventions in achieving broader public health goals [1,2,98].

Across 73 Gavi-supported countries, modeling studies projected that RSV MI could prevent 10 to 12 million RSV cases, 8.5 to 112 million disability-adjusted life years (DALYs), and 123,000 to 177,000 deaths between 2023 and 2035 [99,100]. A 42% reduction in RSV-attributable deaths among infants younger than six months in Gavi countries. Studies conducted in Kenya further indicate that RSV MI could lead to a 32% decrease in RSV infections and a 50% reduction in hospitalizations due to RSV [101,102]. These findings align with projections for other life-saving vaccines, such as the rotavirus vaccine, which averted 36% of rotavirus-related diarrheal deaths among children under five in similar regions. Another modeling study estimated that maternal RSV immunization could significantly reduce the burden of RSV-associated LRTIs among U.S. infants. In the absence of immunization, approximately 590,000 medically attended RSV LRTIs occur annually [103]. Maternal immunization administered year-round is projected to prevent around 74,000 healthcare visits annually, spanning outpatient, emergency department (ED), and hospitalization settings. However, the impact of maternal vaccines may be influenced by their shorter duration of protection, which is assumed to be 90 days. Sensitivity analyses revealed that a 10% increase in maternal vaccine uptake could avert an additional 2,730–16,110 outpatient visits, 820–5,880 ED visits, and 580–2,150 hospitalizations. These findings underscore the potential of maternal immunization to mitigate RSV-related morbidity in early infancy and reduce the associated healthcare burden [22]. The success of maternal RSV immunization serves as a framework for strengthening other maternal vaccine programs. However, gaps in understanding remain, such as differences in vaccine efficacy across income settings, the mechanisms of broader protective effects (e.g., reduced all-cause pneumonia), and logistical challenges in vaccine delivery. Addressing these issues will be vital to maximizing the health benefits of maternal RSV immunization and ensuring equitable access for vulnerable populations [50].

Public health and policy considerations

In 2019, PATH and the WHO released a roadmap to advance maternal RSV immunization (RSV MI), emphasizing the global priority of RSV prevention due to high rates of hospitalizations and deaths, particularly in infants under six months [104]. The roadmap identified gaps in RSV disease data, vaccine efficacy, and health economics, with a focus on supporting LMICs through standardized data collection, funding, and access to WHO-prequalified vaccines. Essential measures include promoting evidence-based decision-making, guaranteeing fair delivery systems, and making sure that vaccinations are accessible, safe, and reasonably priced.

Post-phase III clinical trial data, such as from Novavax, show reduced RSV-related hospitalizations but did not meet primary endpoints. Ongoing clinical questions, such as vaccine efficacy variations between high- and low-income countries, need further exploration. As more data emerge, preparations should focus on raising awareness, enhancing collaboration between immunization and maternal health programs, improving operational readiness, and monitoring local RSV epidemiology and vaccine safety [53]. Despite the inconclusive trial results, maternal immunization offers significant health benefits. Policymakers ought to keep pushing for its inclusion in international health plans, filling up information gaps, and bolstering the use of vaccines in RSV-affected nations. When a maternal RSV vaccination becomes accessible, its application in many contexts depends on further research and operational initiatives. Educating stakeholders about RSV infections and the advantages of maternal vaccination is part of this. Maternal, Neonatal, and Child Health (MNCH) programs, which are frequently in charge of administering vaccines, and Expanded Programs on Immunization (EPI) must collaborate more effectively. Additionally, establishing significant operations and logistics for vaccine procurement, distribution, and monitoring is fundamental, as is setting up systems to track local epidemiology and assess vaccine safety and impact [105,106,107].

Future directions and clinical gaps

In LMICs, where RSV continues to be a major cause for infant morbidity and mortality, maternal RSV vaccination has the potential to significantly reduce the virus’s impact. However, clinical and operational challenges persist. While phase III trials have shown benefits like reduced hospitalizations, questions remain about the mechanisms of protection, especially regarding severe RSV-related pneumonia and hypoxemia. The variability in vaccine efficacy between high- and low-income settings needs further investigation, particularly for preterm infants, who are at higher risk for severe infections. Operationally, the success of maternal RSV immunization in LMICs depends on ensuring safe, effective, and affordable vaccines, strengthening health systems, and improving coordination between maternal health and immunization programs. It’s also essential to develop infrastructure to monitor the epidemiology, safety, and impact of the vaccine once implemented. Future efforts should focus on addressing these gaps, particularly improving vaccine formulations and understanding how vaccines perform across diverse populations. Continued surveillance, real-world data collection, and strengthening immunization systems will be fundamental for the widespread success of maternal RSV vaccination [53].

Conclusions

In conclusion, maternal RSV immunization represents a critical advancement in the prevention of RSV- associated morbidity and mortality, predominantly in high-risk populations like preterm infants, infants under six months, and those residing in low- and middle-income countries (LMICs). The results from clinical trials and modeling studies suggests that vaccinating pregnant women could considerably decrease the global RSV burden by preventing severe infections in infants and minimizing hospitalizations, particularly in regions with limited access to healthcare. By targeting pregnant women, maternal immunization offers an effective strategy to provide passive immunity to infants who are most vulnerable during their early months of life. Furthermore, the positive outcomes from maternal RSV immunization trials could pave the way for similar vaccine strategies in preventing other respiratory infections, such as influenza and pertussis, thereby strengthening maternal immunization programs worldwide. This approach could lead to substantial improvements in public health outcomes, enhancing healthcare access and equity, especially in LMICs where the burden of RSV is highest. Finally, integrating maternal RSV immunization into global health policies could play a pivotal role in reducing the disproportionate mortality and healthcare costs associated with RSV, making it a key intervention in achieving broader health equity and improving overall maternal and child health.