Delineating RSV‐A and RSV‐B: Epidemiological Patterns, Diagnostics, Clinical Severity, and Preventive Approaches

ABSTRACT

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infections globally, particularly affecting infants, older adults, and individuals with chronic conditions. RSV comprises two major antigenic subgroups, RSV‐A and RSV‐B, with RSV‐A traditionally viewed as the dominant, more transmissible, and virulent strain. In this comprehensive review, we synthesize epidemiological, clinical, virological, and immunological evidence to demonstrate that both subgroups co‐circulate worldwide with shifting patterns of dominance and a comparable capacity to cause severe disease. Molecular surveillance shows dynamic genotype evolution in both groups, influencing epidemic patterns and immune recognition. These findings underscore the need for continuous genomic monitoring and the widespread use of broadly protective preventive measures, including vaccines and monoclonal antibodies, that target both RSV‐A and RSV‐B to effectively reduce RSV‐associated morbidity and mortality.

1. Introduction

Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections (LRTIs) worldwide, particularly among infants, older adults, and individuals with underlying chronic conditions, including immune deficiencies. It disproportionately affects individuals in low‐ to middle‐income countries, where limited access to healthcare services combined with numerous clinical, socioeconomic, and environmental risk factors increases susceptibility and severity [1, 2]. Nevertheless, even in high‐income regions, RSV contributes substantially to morbidity and mortality, leading to hospitalizations, increased healthcare burden, and long‐term respiratory sequelae [3].

Nearly all children are infected by RSV within the first 2 years of life, and reinfections can occur throughout life, even during the same epidemic season, reflecting incomplete and transient infection‐induced immunity [4, 5, 6, 7] Severe disease occurs mainly in premature infants, those under 6 months of age, and individuals with underlying health conditions such as congenital heart disease, chronic lung disease, or immunocompromised states [8, 9]. As estimated, annually, RSV can be responsible for more than 30 million LRTI episodes in children younger than 5 years worldwide, resulting in 60,000 deaths [10, 11]. Epidemiologic studies indicate that RSV infection, especially in severe cases during early life, is a significant risk factor for recurrent wheezing and asthma, and has been linked to impaired lung function and recurrent LRTI in adulthood [12, 13]. In adults aged 60 years and older, RSV can also cause LRTIs and exacerbate underlying cardiopulmonary conditions. In the United States alone, RSV accounts for 123,000 to 193,000 hospitalizations and more than 10,000 deaths annually in this age group [14, 15, 16, 17], with comparable age‐specific morbidity reported in Asia and Europe [18, 19]. All in all, the global socioeconomic burden caused by this pathogen is substantial [20, 21, 22].

The management of RSV infection is primarily supportive, focusing on hydration, supplemental oxygen, airway suctioning, and mechanical ventilation when necessary [23]. Ribavirin remains the only antiviral approved by selected agencies (e.g., the Food and Drug Administration in the USA). However, its use is limited by cost, toxicity, and uncertain efficacy, and is generally reserved for severe cases in immunocompromised individuals [24]. Other therapies, such as beta‐adrenergic agents, corticosteroids, and hypertonic saline, may offer symptomatic relief but are not routinely recommended due to their limited benefit [25]. Although several small‐molecule inhibitors and nanobodies are under clinical investigation, none have yet demonstrated consistent real‐world efficacy [26]. Altogether, the limited treatment options and significant global impact of RSV highlight the critical importance of preventive measures.

Currently, these measures include monoclonal antibodies for high‐risk infants and vaccines for maternal and elderly populations with RSV, underscoring the increasing feasibility of targeted interventions. However, effective prevention and surveillance require a nuanced understanding of RSV's viral diversity and evolution. RSV is classified into two major antigenic subgroups, RSV‐A and RSV‐B, defined by differences in the attachment (G) glycoprotein [27]. Each subgroup consists of multiple evolving clades that co‐circulate within a given season. Both subgroups evolve through gradual accumulation of mutations, leading to periodic emergence of new genotypes and potential shifts in epidemic patterns.

Many assumptions persist regarding subgroup‐specific characteristics, with RSV‐A often considered more dominant, transmissible, and clinically severe than RSV‐B. However, evidence for these distinctions is heterogeneous, and their true relevance remains unclear. Therefore, this narrative review critically assesses the current evidence regarding RSV‐A and RSV‐B, challenging common assumptions about their differences in dominance, transmissibility, and clinical severity. To this end, a semi‐quantitative literature review approach was employed, combining database searches (Google Scholar, Web of Science, and Scopus) with subsequent qualitative screening and analysis of the evidence. Boolean searches of peer‐reviewed articles published in English were conducted using a combination of keywords related to RSV‐A and RSV‐B, and epidemiology, diagnostics, clinical outcomes, and preventive measures. By addressing these areas, the review provides a comprehensive overview of the relevance of both RSV subgroups and informs evidence‐based approaches to surveillance, treatment, and prevention.

1.1. Epidemiology and Molecular Diversity of RSV Subgroups

RSV exhibits a marked seasonal pattern, with epidemics typically occurring during the winter months in temperate regions and during the rainy season in tropical climates [28, 29, 30]. While early literature often suggested that RSV‐A predominates globally, accumulating evidence challenges this assumption. The epidemiological landscape of RSV is characterized by substantial temporal and geographical variability, with alternating or region‐specific dominance of the two subgroups rather than a stable global hierarchy.

A growing number of longitudinal and regional studies indicate that RSV‐A and RSV‐B frequently alternate as the predominant subgroups from one season to the next. In some years, RSV‐A clearly dominates; in others, RSV‐B accounts for the majority of detections; and in several settings, both subgroups circulate at comparable levels. This dynamic pattern has been documented across multiple continents. For example, in Poland, RSV‐A and RSV‐B revealed a similar share in infections in the 2022/23 season, a dominance of RSV‐A in 2023/24, and subsequent RSV‐B dominance in 2024/25, showing that subgroup‐specific epidemiological shifts can occur between consecutive seasons [31]. In turn, long‐term surveillance in Beijing, China (2007–2015) revealed a biennial alternation between RSV‐A and RSV‐B dominance [32], whereas in Rome, Italy (2017–2023), RSV‐A prevailed in 2021–2022 and was rapidly replaced by RSV‐B in 2022–2023 [33], similarly as in Bulgaria [34]. In contrast, data from France (2010–2014) and northern Italy (2009–2014) suggested a longer period of RSV‐A predominance, although RSV‐B re‐emerged as the leading subgroup in certain years, such as 2010–2011 [35, 36]. In turn, in Norway (2015–2018), no clear alternation was observed, with both subgroups co‐circulating in relatively stable proportions [37]. Across the Southern Hemisphere, subgroups' dominance also varies. In Australia (2016–2017), a shift was observed from RSV‐B to RSV‐A between successive seasons, echoing patterns seen elsewhere and confirming that both subgroups retain epidemic potential [38].

Surveillance data from the United States illustrate how spatial differences can occur within a single country, as analyses from 2016 to 2020 and 2022–2024 demonstrated marked regional heterogeneity, with RSV‐A prevailing in some states while RSV‐B was more frequent in others during the same season [39, 40, 41]. This decentralized pattern reflects how transmission dynamics and immunity may vary across populations, climates, and healthcare systems. Similar spatial contrasts have been observed globally: a multi‐country analysis for 2017–2018 found RSV‐B predominating worldwide, except in South Africa, where RSV‐A remained the leading subgroup [42]. Taken together, these observations indicate that subgroup dominance is neither fixed nor globally synchronized. A range of factors has been proposed to contribute to these patterns, including population immunity, genotype turnover, transmission dynamics, and environmental conditions (Table 1), although their relative contributions remain incompletely understood.

Table 1.

Potential hypothetical drivers of RSV subgroup dominance.

Driver	Impact	Reference
Population immunity	Immunity against the previously dominant subgroup may promote the rise of the alternate subgroup in subsequent seasons.	[43, 44, 45]
Exposure dynamics	After periods of low RSV circulation (e.g., during COVID‐19 restrictions), reduced population immunity (“immune debt”) can allow one subgroup to dominate once transmission resumes.	[33, 46, 47, 48]
Genotype shifts	Emergence and replacement of genotypes within RSV‐A or RSV‐B can alter subgroup prevalence. Mutations, particularly in the G protein, may enhance transmissibility or immune evasion.	[49, 50, 51]
Positive selection	Amino acid substitutions associated with antibody escape have been demonstrated experimentally and may confer selective advantages to certain genotypes under immune pressure.	[52, 53, 54, 55]
Transmission dynamics	Differences in replication fitness or shedding duration between genotypes may transiently influence subgroup predominance.	[39, 43]
Local factors	Climate, population density, and regional contact patterns can shape subgroup dominance.	[56, 57]
Viral interferences	Concurrent or sequential infections with other respiratory viruses may suppress or facilitate the circulation of a given subgroup.	[58, 59, 60]
Stochastic variation	Unpredictable, random fluctuations contribute to year‐to‐year shifts in subgroup dominance.	[43, 56, 61]

Comprehensive analyses and systematic reviews demonstrate that both RSV‐A and RSV‐B are globally widespread and capable of driving large‐scale epidemics. While some earlier studies appeared to favor RSV‐A, such findings were often influenced by diagnostic sensitivity and sampling differences rather than true biological dominance. With the introduction of multiplex RT‐PCR assays and whole‐genome sequencing, surveillance has achieved greater precision, revealing a more accurate and balanced picture of RSV circulation. The two subgroups co‐circulate persistently, with relative proportions that shift across years and regions in response to changing immunity and viral diversity. There is, therefore, no stable or universal predominance of one subgroup over the other ‐ only a dynamic equilibrium shaped by ecological and epidemiological factors.

In summary, the epidemiology of RSV is dynamic, with the relative dominance of its two subgroups fluctuating across time and geography. The notion of inherent RSV‐A predominance is therefore challenged by evidence of a more balanced system in which both subgroups warrant equal consideration in surveillance and prevention.

1.2. Diagnostics and Molecular Identification of RSV Subgroups

Accurate and timely diagnosis of RSV infection is essential for patient management, outbreak control, and surveillance. Currently, it can be identified using a wide range of diagnostic methods that differ in analytical sensitivity, speed, and practicality. Traditional methods, such as viral culture and immunofluorescence, have largely been replaced by molecular assays, which are now considered the gold standard for clinical diagnosis and epidemiological surveillance.

Molecular assays that target subgroup‐specific regions of the viral genome can routinely differentiate between RSV‐A and RSV‐B with excellent accuracy. Techniques such as locked nucleic acid probe‐based real‐time reverse transcription polymerase chain reaction (RT‐PCR) or duplex probe assays achieve high levels of concordance with sequencing results and are well‐suited for clinical and surveillance applications [62, 63]. Commercial multiplex PCR panels and cartridge‐based rapid molecular systems have also been developed to simultaneously detect RSV and determine its subgroup, with reported sensitivities and specificities exceeding 95% compared to reference methods [63, 64, 65, 66]. The highest sensitivities for RSV detection are generally achieved through the amplification of the N gene, which is highly conserved. However, subgroup differentiation is performed by amplifying the F gene and, less often, the G gene [67, 68, 69, 70].

In addition to these established molecular platforms, newer detection strategies are being developed that allow RSV identification and subgroup discrimination with minimal laboratory infrastructure. Isothermal amplification coupled with CRISPR‐based detection (e.g., RT‐RPA/CRISPR‐Cas12a) has demonstrated the ability to detect and distinguish between RSV‐A and RSV‐B within 40 min [71, 72]. However, in some studies, the sensitivity varied greatly between RSV‐A and RSV‐B, at 73% versus 43%, respectively, with other CRISPR‐based assays achieving similar sensitivities of 77% and 78%, respectively. Paper‐based or toehold‐switch biosensors, when combined with an upstream amplification step, show promising results in achieving subgroup‐specific recognition [73]. These technologies are attractive for decentralized testing because they are rapid, inexpensive, and suitable for field deployment, although most remain in the validation or proof‐of‐concept stage and require further optimization.

The sensitivity and detection limits of these assays can vary slightly between RSV subgroups. Comparative evaluations have demonstrated that multiplex or singleplex RT‐PCR and digital PCR methods yield comparable accuracy for both subgroups, with sensitivities and specificities generally exceeding 95%. However, small differences have been noted in certain digital RNA quantification assays, where sensitivity for RSV‐A was reported at approximately 74%, compared to 78% for RSV‐B, depending on the assay design, target gene, and sample type. In contrast, CRISPR‐based assays have shown more pronounced, albeit modest, differences in detection limits, with some studies reporting limits of detection as low as 10² copies per reaction for RSV‐A and 10³ copies per reaction for RSV‐B. These variations likely reflect differences in primer or crRNA binding efficiency rather than inherent disparities between the subgroups. Paper‐based biosensors also display subgroup specificity, but their analytical sensitivity is determined largely by the amplification strategy used and the sample quality.

Rapid antigen detection tests (RADTs) remain widely available for RSV diagnosis, particularly at the point of care. Although these assays offer quick results, their sensitivity is substantially lower than that of molecular techniques, especially in the elderly, who tend to shed less virus. Meta‐analyses have shown that their pooled sensitivity can be as low as 29% in adult populations, while specificity generally remains high [74]. Notably, RADTs do not consistently show a preference for detecting either RSV‐A or RSV‐B. Instead, their performance depends primarily on the viral load, the timing of sample collection, and the quality of the specimen. Nevertheless, since RADTs are designed to detect F‐protein [70, 75], which is highly similar between RSV‐A and RSV‐B [76], it could be expected that their sensitivity or specificity would be affected by the viral subgroup. Yet, some studies have also reported such differences in pediatric patients, e.g., a sensitivity of 69% for RSV‐A and only 44% for RSV‐B [77]. In turn, research comparing the RADTs' sensitivities when testing nasopharyngeal samples from adults did not reveal meaningful performance disparity between RSV‐A and RSV‐B, with differences falling well within the margin of random sampling variability (±1–3%, depending on the test) [78].

In summary, while rapid antigen tests may show slight, context‐dependent variability in sensitivity for RSV‐B, molecular assays (e.g., RT‐PCR, digital PCR) provide consistently high and comparable accuracy for both subgroups and remain the reference standard (Table 2). Emerging point‐of‐care technologies are promising but require further validation. Test selection should therefore balance speed, accuracy, and resources, with molecular methods being essential for accurate surveillance and patient management where subgroup discrimination is critical.

Table 2.

Sensitivity of RSV detection assays.

Assay	RSV‐A sensitivity	RSV‐B sensitivity	Reference
Rapid antigen test	61%–69%	44%–68%	[77, 78]
RT‐PCR	77%–100%	78%–100%	[62, 63, 72]
Multiplex PCR panel	> 95%	> 95%	[63, 64, 65, 66]
RPA‐CRISPR/Cas12a‐Fluorescence	73%	43%	[71]

1.3. Clinical Impact and Pathogenic Differences Between RSV Subgroups

RSV infection ranges from mild upper respiratory tract illness to severe lower respiratory tract disease, including bronchiolitis and pneumonia. Clinical manifestations vary by age, immune status, and comorbidities. In infants, RSV is the leading cause of hospitalization due to bronchiolitis, frequently requiring supplemental oxygen or mechanical ventilation [79, 80, 81, 82]. Premature infants and those with underlying cardiopulmonary disease are particularly vulnerable to severe disease. In older adults, RSV contributes significantly to morbidity by exacerbating chronic obstructive pulmonary disease (COPD), asthma, and heart failure. Hospitalization rates and mortality among older adults are comparable to, or can exceed, those associated with seasonal influenza and the Omicron lineage of SARS‐CoV‐2 in some cohorts; however, these observations vary depending on the studied population [83, 84, 85, 86].

Although both RSV‐A and RSV‐B are responsible for substantial disease burden, there is a common perception among clinicians and researchers that RSV‐A may be associated with more pronounced clinical manifestations [77, 87]. However, this perception is not consistently confirmed by empirical evidence. Comparative studies examining the two RSV subgroups have produced mixed and often contradictory findings. A comprehensive review encompassing over 40 independent studies from diverse geographical regions concluded that the two RSV subgroups do not exhibit consistent, replicable differences in clinical severity [57]. Of these, 29 studies found no difference in disease severity between RSV‐A and RSV‐B [88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117], two suggested greater severity for RSV‐B [118, 119], and 14 indicated that RSV‐A infections were somewhat more likely to require hospitalization, intensive care, or respiratory support [116, 117, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129]. Further investigations published after this review have also shown no significant association between disease severity and RSV subgroups [37, 130, 131], highlighted poorer respiratory outcomes following RSV‐B infection [132, 133] or marginally higher RSV‐A severity [40]. However, the vast majority of these studies focused exclusively on pediatric populations, and any observed differences were generally small, inconsistent across seasons and locations. Analyses that included adult patients either found no difference in clinical severity and outcomes [86, 106, 110] or yielded inconclusive results [128]. A recent meta‐analysis encompassing data from the 1960‐2025 period suggested that RSV‐B is more frequently implicated in healthcare‐associated outbreaks and is linked with higher attack rates [134]. Importantly, the studies show that case fatality rates were highest in coinfections with both RSV‐A and RSV‐B compared to single‐subgroup infections, indicating additive or synergistic clinical effects [134].

The potential differences in clinical outcomes may reflect the transient predominance of specific RSV sublineages rather than inherent differences in virulence between the two RSV antigenic subgroups. The global molecular epidemiology of RSV over the past two decades illustrates why genotype‐level analysis is essential when interpreting subgroup‐level comparisons. The BA genotype of RSV‐B, first detected in Argentina in 1999 with a characteristic 60‐nucleotide duplication in the G protein gene, rapidly disseminated worldwide and in many regions almost completely replaced previously circulating RSV‐B genotypes [135, 136, 137]. A strikingly parallel phenomenon occurred in RSV‐A following the emergence of the ON1 genotype in Canada in 2010, which carries a 72‐nucleotide duplication in the G protein gene [138]. ON1 spread across Europe, Asia, Africa, and the Americas within only a few years of its initial detection, replacing previous RSV‐A genotypes (e.g., GA2/NA1) [137, 139, 140, 141, 142, 143, 144, 145]. A recent systematic review of > 7,800 genotyped RSV‑A sequences found NA1 (including ON1) and BA as the most frequent global genotypes, with reduced genotype diversity after 2000, consistent with selective sweeps [146]. The convergent evolution of large duplications within the G gene in both subgroups, together with their rapid global expansion and sustained circulation over decades, strongly suggests a selective fitness advantage. Indeed, functional studies indicate that the BA duplication enhances viral attachment and in vitro replication efficiency. This near‐complete replacement of diverse historical genotypes by duplication‐bearing lineages in both RSV‐A and RSV‐B underscores that contemporary RSV epidemiology is increasingly shaped by a small number of globally dominant lineages rather than the broader genotype diversity documented in earlier decades.

Looking ahead, further research should prioritize large‐scale, longitudinal studies incorporating both pediatric and adult populations, as improved molecular diagnostic methods, particularly the growing use of multiplex assays, now enable more accurate detection and differentiation of RSV infections across age groups. Sublineage‐level typing will be essential to elucidate whether variations in clinical outcomes are driven by genetic and antigenic diversity within RSV‐A and RSV‐B, rather than between them. Indeed, recent phylogenetic analyses suggest that disease severity may be more closely linked to specific viral genotypes and amino acid variations, particularly within the G and M2‐2 genes, than to the subgroup identity itself, underscoring the need to integrate genomic surveillance with clinical data [133].

In summary, while RSV‐A or RSV‐B may appear modestly more clinically significant in certain settings or epidemic waves, both subgroups are capable of causing severe disease. Further studies, emplying adult patients are needed as the major focus on subgroup‐specific clinical comparisons have been in pediatric groups. Nevertheless, the observed differences were inconsistent and, when present, small. From a public health and clinical standpoint, this means that current preventive measures, whether maternal vaccination, monoclonal antibody prophylaxis (e.g., nirsevimab, palivizumab), or non‐pharmaceutical interventions, should continue to be applied irrespective of RSV subgroup. Similarly, therapeutic approaches remain uniform, as antiviral candidates under development (such as fusion inhibitors or small interfering RNA‐based therapeutics) target conserved regions of the viral genome or the fusion protein shared between RSV‐A and RSV‐B [147, 148]. Nevertheless, the ongoing molecular and epidemiological surveillance of RSV subgroups remains essential. Shifts in predominance or genetic drift within either subgroup could potentially affect vaccine antigenicity, monoclonal antibody binding sites, or diagnostic assay performance. Maintaining global and regional monitoring ensures the early detection of evolutionary changes that may influence both disease severity and the effectiveness of preventive tools.

1.4. Prevention of RSV‐A and RSV‐B Infections

For decades, pharmacologic prevention of RSV was unavailable, leaving supportive care as the mainstay for managing infection. The introduction of monoclonal antibodies, such as palivizumab, revolutionized prophylaxis for high‐risk infants, significantly reducing RSV‐related hospitalizations. However, their use was limited by high cost and the need for monthly dosing during RSV season.

Recent advances in vaccine development, centered on the stabilized prefusion form of the F (preF) protein [149], the principal target of neutralizing antibodies [7, 150], have opened new avenues for broad RSV prevention. All currently approved vaccines are based on the prefusion F protein of RSV, but they differ in formulation, antigen composition, and the use of adjuvants. Two subunit vaccines employing recombinant prefusion F protein were the first to receive regulatory authorization in 2023 for adults aged 60 years and older: the monovalent, AS01E‐adjuvanted RSVPreF3 OA (Arexvy, GSK), which utilizes the RSV‐A2 strain‐derived antigen [151], and the non‐adjuvanted bivalent RSVpreF (Abrysvo, Pfizer), incorporating F proteins from RSV‐A2 and RSV‐B [152]. This was followed in 2024 by the approval of the monovalent mRNA vaccine mRNA‐1345 (mRESVIA, Moderna), which encodes a stabilized prefusion F protein from the RSV‐A2 strain and was similarly indicated for older adults [153]. All of these vaccines demonstrated over 80% efficacy in preventing RSV‐associated lower respiratory tract disease [151, 152, 153], though direct head‐to‐head comparison is not possible due to different outcome definitions employed in the clinical trials [154]. In addition, non‐adjuvanted bivalent RSVpreF vaccine was also authorized for maternal immunization during pregnancy to confer passive protection to infants [155]. Moreover, novel long‐acting monoclonal antibodies targeting a conserved epitope on the F protein ‐ nirsevimab (authorized in 2023) and clesrovimab (approved in 2025) ‐ requiring only a single seasonal intramuscular dose, are poised to further transform prevention strategies in infant populations [156, 157, 158, 159, 160].

Although all three are based on preF, they employ different stabilization strategies to prevent refolding into the postfusion conformation, which induces weaker neutralizing responses [7]. RSVPreF3 OA uses a disulfide bridge (S155C‐S290C) and cavity‐filling mutations (S190F‐V207L) [161, 162]. The bivalent RSVpreF construct uses a distinct disulfide bridge (T103C‐I148C), a cavity‐filling mutation (S190I), and a charge‐neutralizing mutation (D486S) [162, 163]. The mRNA‐1345‐encoded antigen incorporates the S155C, S290C, S190F, and V207L mutations, plus two further mutations (A149C, Y458C) and a modified F1 domain [164]. However, whether the distinct stabilization strategies translate into meaningful differences in immunogenicity or clinical performance remains to be determined

Data from clinical trials suggest subtle efficacy differences between subgroups. In phase 3 trials, the monovalent RSVPreF3 OA vaccine demonstrated efficacy of 84.6% for RSV‐A and 80.9% for RSV‐B in preventing lower respiratory tract disease, and 71.9% versus 70.6% for acute respiratory infection, indicating minimal differences between the two [165]. However, over two seasons, the combined efficacy against lower respiratory tract disease was 80.5% for RSV‐A and 59.7% for RSV‐B [166]. A three‐season analysis reported cumulative efficacies of 69.8% against RSV‐A and 58.6% against RSV‐B lower respiratory tract disease [167], suggesting a moderately greater waning of protection against RSV‐B over time, possibly reflecting a greater reliance on cross‐reactive adaptive responses rather than subgroup‐specific immunity to RSV‐B. In turn, the monovalent mRNA‐1345 vaccine showed somewhat lower protection against RSV‐B, with efficacy of 91.7% (RSV‐A) versus 68.5% (RSV‐B) for lower respiratory tract disease with ≥ 2 symptoms, and 78.5% (RSV‐A) versus 51.7% (RSV‐B) for acute respiratory disease [153]. By contrast, a bivalent RSVpreF vaccine demonstrated efficacy against the first episode of lower respiratory tract infection with ≥ 3 symptoms caused by RSV‐A and RSV‐B of 80.0% and 91.7%, respectively, during the first season, and 80.8% and 80.0%, respectively, during the second season [168]. This more balanced protection between RSV‐A and RSV‐B across seasons may reflect the benefit of including antigens representing both subgroups in the vaccine formulation.

Although the RSV F protein, the primary target of current vaccine antigens, is highly conserved between subgroups, small but distinct antigenic differences exist, with amino acid sequence divergence of approximately 10% [169]. These minor structural variations may influence neutralizing antibody binding and could partially account for the modestly lower efficacy observed against RSV‐B in some formulations, particularly those derived from RSV‐A F protein sequences. Moreover, a study conducted in the United States between 2015 and 2019 found that amino acid changes at key antigenic sites of the F protein occurred more frequently in RSV‐B than in RSV‐A, particularly at sites V, Ø, and IV, suggesting greater antigenic plasticity of RSV‐B, which could further impact vaccine‐induced immunity [170]. Indeed, the emergence of mutations in RSV‐B, leading to 2‐amino acid epitope substitution, was previously responsible for the failure of suptavumab, a monoclonal antibody targeting the prefusion F protein, in a phase 3 clinical trial that demonstrated protective efficacy against RSV‐A but not RSV‐B [171]. Such observations highlight the importance of continuous monitoring of immune escape mutations, particularly in the context of the expanding use of monoclonal antibodies, such as nirsevimab, as well as prophylactic RSV vaccines.

The bivalent vaccine constructs or antigen designs incorporating representative F proteins from both subgroups may potentially offer a more balanced breadth of protection. A conceptual overview of cross‐reactive antibody responses induced by monovalent and bivalent prefusion F vaccines is shown in Figure 1. As shown, both monovalent and bivalent vaccines targeting the F protein elicit cross‐neutralizing antibodies and provide protection against RSV‐A and RSV‐B in animal models and humans. However, immune responses can be heterogeneous, and the duration of protection against RSV‐B may be somewhat shorter for monovalent vaccines [168, 172, 173, 174]. For example, mRNA‐1345 induced an 8.4‐fold increase in neutralizing antibodies for RSV‐A and a 5.1‐fold rise for RSV‐B, with corresponding seroresponse rates of 74.2% and 56.5%, respectively [175, 176]. This vaccine also generated Th1‐skewed CD4⁺ and CD8⁺ T‐cell responses, which were generally higher for RSV‐A, reflecting its RSV‐A‐derived antigen [175, 176, 177]. Similar trends were observed with other monovalent preF‐based vaccines, in which neutralizing titers increased by 9.4‐11.3‐fold for RSV‐A and by 8.0‐9.0‐fold for RSV‐B 1 month post‐vaccination [178]. The adaptive cellular responses were consistently Th1‐polarized and associated with elevated frequencies of RSV F‐specific CD4⁺ T cells and enhanced neutralization titers for both subgroups, though again slightly favoring RSV‐A [178, 179, 180]. In contrast, bivalent vaccines containing both RSV‐A and RSV‐B preF antigens achieved nearly equivalent neutralizing titers against both subgroups, with geometric mean fold rises of 11.6‐13.0 for RSV‐A and RSV‐B [168]. They also elicited robust, Th1‐biased CD4⁺ T‐cell responses producing IFN‐γ, with comparable magnitude for each subgroup [168, 181]. This balanced immune profile likely results from the inclusion of both A and B antigens, mitigating the bias toward the homologous subgroup observed with monovalent formulations.

Figure 1.

Humoral responses induced by monovalent and bivalent prefusion F (preF) RSV vaccines. (A) Monovalent vaccination based on an RSV‐A–derived prefusion F antigen induces neutralizing antibodies primarily directed against RSV‐A. Because the F protein is conserved between RSV subgroups, these antibodies can also exhibit cross‐reactivity with RSV‐B. (B) Bivalent vaccination containing prefusion F antigens from both RSV‐A and RSV‐B stimulates the production of subgroup‐specific antibody populations that can neutralize their homologous antigenic subgroups while also maintaining cross‐reactive activity between subgroups. Graph created with BioRender.com.

Currently, real‐world effectiveness studies assessing vaccine impact primarily focus on aggregate outcomes, such as the prevention of RSV‐associated lower respiratory tract disease, hospitalization, or severe illness, without differentiating between RSV subgroups. As diagnostic and sequencing tools continue to evolve, future research should aim to disaggregate these outcomes by viral subgroup, enabling a more refined understanding of vaccine performance, the durability of protection, and potential subgroup‐specific differences in immune escape. Such data will be crucial in guiding the optimization of next‐generation vaccine formulations and informing global surveillance strategies. Moreover, genetic variation within subgroups may influence neutralizing antibody binding, viral fitness, and susceptibility to monoclonal antibodies or vaccine‐induced immunity. Consequently, integrating genomic epidemiology with vaccine and monoclonal antibody effectiveness studies will be critical to detect potential genotype‐specific differences in protection and to identify emerging variants that could affect the performance of current preventive tools.

Taken together, current evidence indicates that prefusion F‐based vaccines elicit strong and broadly cross‐reactive immunity to both RSV subgroups, consistent with the clinical protection demonstrated by licensed vaccines. Although formulations based on an RSV‐A prefusion F sequence may show a bias toward stronger neutralizing responses against RSV‐A, this does not preclude meaningful protection against RSV‐B. Bivalent formulations may provide more balanced neutralization profiles and could further broaden subgroup coverage at the population level. Further real‐world studies are needed to determine whether these immunogenicity differences translate into measurable differences in vaccine effectiveness against RSV‐A and RSV‐B disease.

2. Conclusions

Both RSV‐A and RSV‐B co‐circulate globally, with variable dominance that shapes epidemic patterns. While RSV‐A is often assumed to be more transmissible or clinically severe, evidence for consistent subgroup‐specific differences is lacking and is likely complicated by host and environmental factors. Consequently, pharmacological interventions, including vaccines and monoclonal antibodies, should continue to be designed, monitored, and evaluated for protection against both subgroups to ensure comprehensive prevention of RSV‐related morbidity and mortality.

Author Contributions

Piotr Rzymski conceptualized the work and wrote the original manuscript. Barbara Poniedziałek, Dorota Zarębska‐Michaluk, Lidia Brydak, Teresa Jackowska, Adam Antczak, Krzysztof Tomasiewicz, and Robert Flisiak provided critical intellectual input, reviewed the manuscript, and contributed to its revision. All authors read and approved the final version of the manuscript.

Ethics Statement

This study is a narrative literature review and does not involve the collection of primary data from human participants or animals. All information analyzed in this review was obtained from previously published sources available in the public domain. Therefore, ethical approval from an institutional review board or ethics committee was not required.

Conflicts of Interest

P.R. reports grants, consultancy, advisory roles, lecture fees from Pfizer, an advisory role for Moderna, and lecture fees from Sanofi. D.Z.‐M. reports lecture fees from AbbVie, Gilead, Pfizer, and Roche Diagnostics, as well as an advisory role for Moderna. T.J. reports lecture fees from Pfizer and lecture fees from Sanofi and an advisory role from Sanofi. K.T. reports research, advisory role, and lecture honoraria from AbbVie, Bausch HealthCare, Boehringer Ingelheim, Gilead, and Pfizer. R.F. reports research grants, lecture honoraria, and an advisory role for AbbVie, Gilead, and Pfizer, as well as an advisory role for Moderna and NovoNordisk.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.