Immune and Virological Factors Influencing Human Respiratory Syncytial Virus Circulation and Increased Prevalence During and After the COVID-19 Pandemic

Abstract

Human respiratory syncytial virus (hRSV) is a leading cause of respiratory infections in infants and older adults. The COVID-19 pandemic disrupted hRSV transmission due to non-pharmaceutical interventions (NPI), resulting in atypical circulation patterns, earlier seasonal peaks, and increased post-pandemic prevalence. Two key factors are proposed to underlie these changes: a reduced specific immune response due to decreased viral exposure and the emergence of novel hRSV variants. These factors contributed to a larger cohort of immunologically naïve children and lower levels of maternally derived antibodies, increasing susceptibility to severe hRSV disease, particularly in infants and children. Additionally, adults experienced waning immunity following prolonged periods of limited hRSV circulation. The post-pandemic resurgence was accompanied by the emergence of novel hRSV variants with altered transmissibility and virulence, such as GB5.0.6a in Europe and B.D.E.1 in China. These variants may reflect mutations driven by the reduced immunity, though further research is needed to assess their pathogenicity. Understanding the interplay between the reduced immunity due to NPI and virological factors is essential for addressing hRSV epidemiology. Enhanced molecular surveillance and immunological monitoring are crucial for guiding vaccination strategies and protecting vulnerable populations against future hRSV outbreaks.

Keywords

human respiratory syncytial virus hRSV atypical transmission viral genotypes COVID-19 pandemic waning immunity

Introduction

Human respiratory syncytial virus (hRSV) has been recognized since its identification as a leading cause of acute lower respiratory tract diseases, such as bronchiolitis and pneumonia in children under 5 years of age. However, the highest burden of morbidity and mortality is in infants aged 0–6 months (Li et al., 2022). Adults aged 60 years and older are also at high risk of developing severe hRSV disease, with an estimated annual incidence of 4.6%. This risk increases to 7.0% in adults with underlying medical conditions such as diabetes, congestive heart failure, and chronic obstructive pulmonary disease (Havers et al., 2023; Nguyen-Van-Tam et al., 2022).

hRSV is an enveloped, negative-sense single-stranded RNA virus that encodes ten genes and expresses 11 proteins (NS1, NS2, N, P, M, SH, G, F, M2-1, M2-2, L) with structural, regulatory and immune evasion-related functions (Schmidt and Varga, 2017; Sutto-Ortiz et al., 2023). Since 1962 two antigenic groups, hRSV A and hRSV B, were identified through cross-neutralization assays (Sullender, 2000). This classification has been maintained after studying the virus genome, particularly based on significant differences in the sequence of the G protein gene between both subgroups (Yu et al., 2021).

Before the coronavirus disease-2019 (COVID-19) pandemic, the seasonal transmission of hRSV was relatively well-defined. During the COVID-19 pandemic, hRSV transmission diminished from very low to undetectable levels, since non-pharmaceutical interventions (NPI) not only prevented SARS-CoV-2 transmission but also reduced circulation of other respiratory viruses. After NPI for COVID-19 were suspended, inter-seasonal transmission of hRSV and increased hospitalizations followed. Herein, we review the epidemiological data on the atypical transmission patterns of hRSV during the COVID-19 pandemic, the groups most affected after the viral resurgence and the risk factors involved. We also describe the differential circulation of hRSV subtypes A and B. Finally, we examine the main factors contributing to the increased incidence of hRSV after the COVID-19 pandemic, including potential mechanisms associated with a diminished immune response or “immunity debt” resulting from prolonged reduced hRSV exposure, and the emergence of more transmissible or virulent hRSV strains. The relative contribution of waning population immunity versus novel hRSV variants to the rise in hRSV prevalence and hospitalizations is discussed.

Clinical Manifestations

In children under 2 years of age, mild hRSV disease is the most common presentation, accounting for 51% of cases, compared to 39% with moderate and 6% with severe disease. However, the incidence of moderate and severe disease among infants under 1 year is 50% and 9%, respectively (Jiang et al., 2023). In fact, oxygen supplementation is required in 54% of infants aged 0–1 year and 26% of children aged 0–2 years. In addition, there is a significant positive association between hRSV infection and developing recurrent wheezing (OR = 3.12, 95% CI 2.59–3.76). Adults with chronic medical conditions can also develop wheezing and dyspnea with frequencies of 20% and 47%, respectively (Galindo-Fraga et al., 2024; Kenmoe and Nair, 2024). The incidence of the common clinical manifestations is summarized in Figure 1 (Jiang et al., 2023).

FIG. 1.

Incidence of symptoms during human respiratory syncytial virus (hRSV) infection in children <2 years, according to a systematic review and meta-analysis by Jiang (Jiang et al., 2023).

Pre- and Post-Pandemic Transmission of hRSV

Before the COVID-19 pandemic, hRSV transmission in countries of the northern hemisphere typically started between epidemiological weeks 45 and 3, lasted for 10–17 weeks, and ended between weeks 6 and 13. In countries of the southern hemisphere, transmission started between epidemiological weeks 3 and 23, continued for 11–15 weeks, and ended between weeks 16 and 36 (Staadegaard et al., 2021).

During the global lockdown in 2020, transmission of hRSV and other respiratory viruses were reduced to very low levels; some countries registered a hRSV positivity from 0 to 0.2% (Bardsley et al., 2023; Debbag et al., 2024; Fourgeaud et al., 2021; Hönemann et al., 2024; Lastrucci et al., 2024). However, after NPI were no longer mandatory, inter-seasonal transmission of hRSV was observed, accompanied by altered incidence patterns.

For example, in England, hRSV pre-pandemic transmission typically peaked in weeks 47–50. However, after undetectable levels were registered during the 2020–2021 season, a resurgence was observed in the summer of 2021, with 13.6-fold increase in positivity rates and 10.7% increased hospitalizations (Bardsley et al., 2023). In Paris, France, the typical peak of hRSV transmission occurs between October and January. However, during the 2020–2021 season, hospitalizations did not begin until December 2020, with a delayed peak observed in February–March 2021. Notably, this study reported that acute lower respiratory infections (ALRIs) were more frequent in infants aged 6 to 11 months (25.8%) compared to pre-pandemic seasons, when the prevalence in this age group was approximately half (13.1%). Conversely, the prevalence in infants under 6 months decreased from 56.6% to 41.3% (Fourgeaud et al., 2021).

In Italy, the pre-pandemic hRSV pattern of seasonality typically began in November, peaking in late January or early February and ending in March. During the 2021–2022 season, virus transmission started approximately one month earlier and lasted for 12 weeks, with a 4.6-fold increase in hospitalizations for severe disease among children aged 12 months or older compared to pre-pandemic seasons (Lastrucci et al., 2024).

Similarly, a cross-sectional study that analyzed data from 48 pediatric hospitals in the USA reported an hRSV resurgence in 2022–2023, with an 86.7% increase in hospitalizations, a 43% rise in intensive care unit (ICU) admissions and 28.3% increase in total deaths. Also, the burden of hRSV disease were prevalent in older children, with a median age of 11.3 months compared to 6.8 months in the pre-pandemic seasons (Winthrop et al., 2024). This increase in disease burden and the median age of hRSV-positive infants were consistent with findings from other studies (Falsaperla et al., 2024; Foley et al., 2022; Piñana et al., 2024).

The inter-seasonal hRSV transmission occurred in some regions during spring and summer, albeit high temperatures normally diminish the risk of virus transmission (Guo et al., 2021). Possibly, full reopening of schools after suspension of NPI compensated for the temperature effects, increasing 23-fold the risk for hRSV transmission in warmer seasons (Li et al., 2022; Mosscrop et al., 2022), especially in infants of the same family, contributing to the unusual morbidity after season 2021–2022 (Munywoki et al., 2014). Thus, earlier or delayed peaks of hRSV infection were observed after relaxation of NPI, along with an overall increase in incidence and disease severity. These post-pandemic trends may be explained by the cohort of susceptible children experiencing their first hRSV exposure at an older age, having remained immunologically naïve during the period of reduced viral circulation (Lastrucci et al., 2024). An additional explanation for the changes in disease severity and viral transmissibility is the temporary decline in hRSV variant diversity due to reduced international mobility during the lockdown, followed by the resurgence of new more virulent variants (Eden et al., 2022).

hRSV and Other Respiratory Viruses

The increased need for SARS-CoV-2 surveillance resulted in the rise in the number of samples available for differential diagnosis and monitoring of other respiratory pathogens, thereby enhancing epidemiological data. In Mexico, a descriptive study conducted from 2017–2023 that determined the viral etiology of respiratory diseases, reported that hRSV were the most prevalent virus in infants, followed by rhinovirus, metapneumovirus, parainfluenza virus 2, bocavirus and adenovirus (26.3%, 24.8%, 10.1%, 8.7%, 7.0%, and 6.9%, respectively) (Hernández Bautista et al., 2024). In 2020, only 35 hRSV-positive cases were confirmed; however, during the 2022–2023 season, hRSV positivity increased 2.7-fold compared with pre-pandemic seasons (Hernández Bautista et al., 2024). Coinfections with other respiratory viruses were detected in approximately 17.0% of samples and occurred more frequently in children under five years of age, consistent with trends in other countries such as Italy (Falsaperla et al., 2024) and the USA (Hayek et al., 2023; Weidmann et al., 2023).

A retrospective study conducted from January to December 2021 in children and teenagers aged 0 to 21 years from Atlanta, Georgia, reported the following positivity rates: rhinovirus/enterovirus 32.73%%, hRSV 12.88%, SARS-CoV-2 7.64% and adenovirus 6.85%. Notably, there was a low proportion of coinfections between SARS-CoV-2 and other respiratory viruses (1.81%), with the most common coinfections being by rhinovirus (15.69%), adenovirus (4.23%), and hRSV (3.07%). In this study hRSV exhibited an atypical peak in August 2021, coinciding with the predominance of the SARS-CoV-2 Delta variant (B.1.617.2) (Westbrook et al., 2023). Thus, coinfections between hRSV and the Delta variant were infrequent and predominantly detected in children with a mean age of 4.33 years (Westbrook et al., 2023). At that time, the global pooled seroprevalence of SARS-CoV-2 in children and adolescents was 25.63%, suggesting relatively low SARS-CoV-2 transmission in pediatric populations (Naeimi et al., 2023).

On the other hand, compared to SARS-CoV-2 positive participants, coinfections with other respiratory viruses in SARS-CoV-2 negative subjects were more common, particularly with rhinovirus and hRSV (>2.0-fold) (Westbrook et al., 2023). In Europe, coinfection of hRSV and SARS-CoV-2 was also observed at a low incidence (reported data indicate 0.29–0.80%) and was not associated with severe respiratory disease (Fourgeaud et al., 2021; Lastrucci et al., 2024).

Differential Transmission of hRSV Subgroups and Variants

Before the COVID-19 pandemic, antigenic hRSV subgroups A and B circulated simultaneously, with a general predominance of hRSV A. In this regard, a systematic review that included 76,668 hRSV A and 30,678 hRSV B samples from 83 countries and from 58 epidemic seasons (from 1961 to 2019), validated the simultaneous detection of both subgroups with the predominance of hRSV A in 43 seasons (74%). The 1969–1970 season had only one positive sample for hRSV B, while in the 1966–1968 and 2016–2017 seasons, detections of both subgroups were similar. Few seasons with global predominance of hRSV B were alternated with consecutive periods of hRSV A transmission (Cantú-Flores et al., 2022). Analysis of the differential transmission by country revealed that in 11 nations, mainly from Asia and Africa, the total number of hRSV B positive samples exceeded that of subgroup A, by a factor ranging from 1.1 to 5.9 (Cantú-Flores et al., 2022).

During the COVID-19 pandemic, the dynamics of hRSV genetic variation were significantly reduced, probably due to the low circulation of the virus during the implementation of measures to limit the transmission of SARS-CoV-2. However, a rapid expansion of hRSV B occurred afterwards in some regions of Europe, Asia, and North America (Evans et al., 2024; Piñana et al., 2024; Rice et al., 2025; Rios-Guzman et al., 2024; Wei et al., 2024). Several studies have suggested that infection with either hRSV A or B subgroups is not consistently associated with differences in disease severity (Bøås et al., 2024; Bonnin et al., 2024; Fodha et al., 2007; Hornsleth et al., 1998; Jafri et al., 2013; Laham et al., 2017; Shen et al., 2022). Nonetheless, some genotypes or variants have been linked to a higher risk of hospital admission (Martinello et al., 2002).

In Italy and Austria, the 2022–2023 season was characterized by an increase in elderly patients infected with the hRSV B genotypes GB5.0.5a and GB5.0.6a compared with the previous season (Pierangeli et al., 2024; Redlberger‐Fritz et al., 2023). In China, transmission of a new hRSV B lineage (denoted B.D.E.1) was detected as of April 2023, becoming prevalent by November of the same year.

It is worth noting that the criteria for hRSV classification are not yet standardized, making global surveillance and comparison between studies challenging. However, recent proposals have been made to define genotypes (according to the G-ectodomain sequence) and lineages (defined from complete genomes to identify phylogenetic clades by signature amino acids) (Goya et al., 2024, 2020).

The B.D.E.1 lineage, which has been identified within the GB5.05a clade (Yunker et al., 2024), were associated with a threefold increase in infections in the group of patients ≥60 years in China, compared with its parental lineage B.D.4.1. Even though the hRSV A lineage A.D.5.2 were also identified, B.D.E.1 were mostly associated with development of upper respiratory tract infections and non-severe pneumonia, in contrast to the severe diseases caused by the previously hRSV dominant lineages (A.D, A.D.3, and B.D.4.1) (Fig. 2) (Wei et al., 2024).

FIG. 2.

Transmission of hRSV subgroups and lineages in pre-pandemic and post-pandemic periods. Before COVID-19 pandemic, hRSV A was predominant with respect to hRSV B. At least three lineages identified in each period are listed, and those prevalent are in bold. Some lineages detected during the hRSV resurgence in 2021 are indicated in gray. (Rice et al., 2025; Wei et al., 2024). Season 2022–2023 was characterized by hRSV B prevalence. Representative characteristics of the B.D.E.1 lineage are mentioned. Created with Biorender.

In Myanmar, the lineages A.D.3 and B.D.4.1.1 were identified in children (<5 years old) through the period 2019–2023, although detection of hRSV B were interrupted in 2020–2022. Similarly to other countries, the hRSV B variant B.D.E.1 were introduced in 2023 producing high rates of infection, in addition to symptoms associated with severe disease (e.g., dyspnea), particularly in children and immunocompromised patients (Fig. 2) (Li et al., 2025; Zhang et al., 2025). Phylogenetic and molecular evolutionary analysis indicated that the pre- and post-pandemic hRSV A and hRSV B variants conserved their evolutionary rate (Li et al., 2025). Nevertheless, the emergent variants might be associated with higher transmission rates and virulence (Zhang et al., 2025). Further virological and molecular studies with B.D.E.1 and other novel viral variants are necessary to support this hypothesis.

Immune Response to hRSV

Innate immune response

hRSV mainly infects epithelial ciliated cells of the human respiratory tract activating macrophages and dendritic cells. The nucleic acids and proteins of hRSV, as fundamental structural components, are key in inducing an innate immune response mediated by activation of NFkB and the IFN regulatory transcription factors 3 and 7. This activation leads to the production of pro-inflammatory cytokines and type I interferons (IFN-I), initiating the host inflammatory response (Correa et al., 2023; Hanada et al., 2018). Airway epithelial cells recognize viral pathogen associated molecular patterns through pattern recognition receptors (PRRs) and cytosolic sensors. TLR-4 and TLR-2 contribute to inflammasome activation (Segovia et al., 2012), while TLR-3 and TLR-7 located in endosomal compartments play key roles in viral RNA sensing (Aeffner et al., 2011). In addition, retinoic acid-inducible gene-I-like receptors (RLRs) and NOD-like Receptors (NLRs) are involved in detecting viral components and induce the antiviral immune response (Attaianese et al., 2023; Da Silva et al., 2023). Although cellular activation through PRRs initiates the antiviral response, it may also induce immunopathology (Tahamtan et al., 2021). The cells and their main functions involved in the innate immune response to hRSV are summarized in Table 1.

Table 1.

Cells Involved in the Innate Immune Response against hRSV

Cell type	Role	References
Epithelial cells	Initial infection; production of antiviral cytokines	Zhang et al., 2002
Alveolar macrophages	Phagocytosis; production of chemokines and cytokines	Wang et al., 2022
Neutrophils	Reactive oxygen species (ROS) and Neutrophil Extracellular Traps (NETs) production for viral elimination; contribution to immunopathology	Sebina and Phipps, 2020
Dendritic cells	Viral antigen presentation to T cells	McDermott et al., 2011
NK cells	Killing of infected cells; immune regulation	Reilly et al., 2024

hRSV, Human respiratory syncytial virus.

Adaptive immune response

Both T (CD4⁺ and CD8+) and B cells are activated during hRSV infection and different viral antigens are involved in the process. Recent findings suggest that the cellular immune response is sufficient to eliminate hRSV in lung tissue in the absence of a specific humoral response (De et al., 2023). During acute infection, a transient lymphopenia is observed, which associates with disease severity and is inversely correlated with age (Attaianese et al., 2023; Russell et al., 2017). These findings highlight the importance of the T cell response during hRSV infection. Accordingly, infants with low respiratory tract infection that require mechanical ventilation, have reduced percentages of effector CD8+ T cells with a concomitant increase in severity and viral load. During the recovery phase, specific CD8+ T cell response increases (Lukens et al., 2010). The nucleoprotein N and the F protein have been characterized as immunodominant antigens to induce specific CD4⁺ and CD8+ T cells (Papayanni et al., 2023). hRSV infection in infants under 6 months of age is associated with higher rates of hospitalization compared to older infants. This increased susceptibility may be partially explained by immunological immaturity, including lower levels of CD8+ T cells in the respiratory tract, which are critical for viral clearance (Hartmann et al., 2022; Ruckwardt et al., 2016; Welliver et al., 2007).

The envelope G and F proteins are necessary for hRSV entry into the ciliated epithelial cells (Johnson et al., 2015; Levine et al., 1987; Neal et al., 2024; Zhivaki et al., 2017). The G protein binds to CX3CR1 and glycosaminoglycans during attachment to the cell membrane, while the F protein can interact with ICAM-1, epidermal growth factor receptor, insulin-such as growth factor 1 receptor and nucleolin to mediate viral entry by fusion of the viral envelope with the cellular membrane (Feng et al., 2022; Johnson et al., 2015; Zhivaki et al., 2017). These two envelope proteins are mainly responsible for the generation of neutralizing antibody responses with different subgroup specificities. hRSV A and hRSV B are phylogenetically and antigenically different (Attaianese et al., 2023; Russell et al., 2017). The G glycoprotein shows the highest variability defining the hRSV subgroup. In contrast, the F glycoprotein shows less than 10% of sequence diversity between both subgroups and induces cross-reactive antibodies (Bohmwald et al., 2016; Sande et al., 2013).

Neutralizing antibodies primarily target the F protein, which may exist in two conformations: in a metastable pre-fusion configuration, prior to interacting with its cellular receptor, and in a highly stable post-fusion conformation (Magro et al., 2012). Six antigenic sites (ø and I–V) have been recognized in F, although sites ø and V are exclusively present in the pre-fusion conformation. Antibodies targeting these two regions exhibit a broad neutralizing activity (McLellan, 2015). The presence of maternally transferred neutralizing antibodies delivered via the placenta and through colostrum has been associated with a reduced risk of severe disease in this age group. These antibodies likely reduce disease severity during the first months of life, when the infant’s immune system is developing (Buchwald et al., 2021; Ogilvie et al., 1981). Although hRSV-specific IgG antibodies are detectable in mothers of infants under 3 months of age hospitalized with bronchiolitis, antibody titers are significantly lower compared to those in mothers of non-hospitalized infants. These findings suggest that lower maternal antibody titers may be associated with susceptibility to severe disease, but further studies are needed to define a threshold that is effective in conferring protection (Coindy et al., 2024; Englund, 1994; Koivisto et al., 2022).

A study comparing serum antibody levels during both acute and convalescent phases of infection in infants <12 months found higher antibody levels and neutralizing activity during the convalescence phase. However, this increase was observed predominantly in infants who did not develop severe disease. In contrast, infants ≤2 months of age did not exhibit a significant increase in neutralizing antibodies between acute and convalescence phases. This deficient response might be attributed to an immature immune system or suppression by maternally derived antibodies (Bonnin et al., 2024). These findings underscore the importance of maternally derived protection, which can be enhanced through maternal immunization to achieve effective antibody titers. Thus, passive transfer of these antibodies can protect against severe hRSV infection. Maternal vaccination is therefore recommended to enhance neutralizing antibodies titers in early infancy, potentially delaying or reducing severe disease during the first 6 months of age, when the immune system and airways are still immature (Buchwald et al., 2021; Cai et al., 2024).

High affinity neutralizing antibody titers result from continued exposure to hRSV in older children (Sande et al., 2014). However, these antibodies fail to protect for recurring hRSV infection throughout life (Lambert et al., 2014). In fact, reinfections have been documented in adult volunteers previously infected with hRSV through experimental virus challenge studies. Under such conditions, the initial challenge resulted in symptomatic infections in 85% of the subjects. However, subsequent experimental challenges led to more than 50% of individuals remaining asymptomatic, with reduced viral titers and less days of virus shedding. Notably, reinfection with the same hRSV strain occurred in 25% of subjects despite high levels of specific antibodies, although those with detectable nasal IgA were less frequently infected (Hall et al., 1991). Thus, IgA and IgG are correlated with protection and recovery not only in infants but also in adults during hRSV reinfections (Tsutsumi et al., 1995).

In elderly patients with nosocomial hRSV infection, elevated levels of IgG and IgA titers are observed, probably associated with increased viral replication rather than indicating effective protection (Agius et al., 1990). This suggests that antibody levels alone may be insufficient to prevent severe disease. The protective efficacy of hRSV-specific antibodies appears to depend not only on concentration or neutralizing capacity but also on their avidity. A critical role for antibody avidity in effective protection against hRSV has been demonstrated. Additionally, TLR activation in B cells is essential for affinity maturation and the generation of high-avidity protective antibodies (Delgado et al., 2009).

Immune Response to hRSV During the COVID-19 Pandemic

As previously mentioned, the usual winter seasonality of hRSV was notably modified during the first 2 years of the COVID-19 pandemic, along with a near-disappearance of hRSV detection in 2020 in most countries from the north and south hemispheres. (Foley et al., 2022; Li et al., 2022b; Mosscrop et al., 2022). Specific hRSV immune responses were also affected. For example, in British Columbia, Canada, the reduced exposure to hRSV was associated with a decline in antibody levels in infants and women of childbearing age in 2020 and 2021. Although anti-F IgG levels showed a slight decrease in women of childbearing age in this period, the reduction in 4–11-month-old infants in 2021 was 15-fold, probably due to waning of maternal immunity. Infants with no memory T and B cells depend on maternally derived antibodies for hRSV protection. It is suggested that because of the lack of hRSV exposure, infants under 2 years of age showed an increased risk of hospitalization (Reicherz et al., 2022).

In a prospective study in the Netherlands analyzing the post-fusion F IgG antibodies in 558 randomly selected participants, a decline in antibody production during the COVID-19 pandemic was observed. Sera were collected at 3 timepoints: T1, several months after NPI implementation (in June 2020), T2, 1 year after the typical hRSV season, and T3, in June 2021, when NPI were lifted. Specific antibody levels significantly declined from 2020 to 2021 across all age groups, except in those aged 31–40 (Den Hartog et al., 2023). The decline in antibody titers was also observed in a study in China where samples from 368 children under 5 years of age were prospectively collected between February 2021 and 2023. The study showed infants aged 1–5 months had higher antibody levels than those aged 6–11 months, with no significant decline in either group during 2021–2023.

In contrast, a significant reduction of specific antibody levels was observed in older children aged 1–4. These data could explain the surge of hRSV cases in older children compared to pre-pandemic seasons and suggest that younger infants could still be protected by maternally transferred antibodies. Although more positive hRSV cases were observed in 2021 and 2023 in all age groups, especially in older children, no increase in hRSV-associated ICU admissions was identified (Jiang et al., 2024).

Another prospective study involving 189 adult participants from a rural town in Germany, conducted from May 2020 to May 2021, showed no decline in antibody production (Pletz et al., 2022). These conflicting results could be due to differences in the analyzed antibodies, the age of the study population, the timing of the sampling relative to NPI implementation, differences in hRSV circulation, and the number of reinfections.

Mechanisms Associated with Diminished Immune Response to hRSV During COVID-19

Unlike viruses with a systemic pattern of infection in their hosts, infections by respiratory viruses are usually transient and localized to the respiratory epithelium, inducing short-lasting immune responses. As a result, reinfections are common and may not only be associated with waning immunity, but also with viral immune escape, as observed in RNA viruses such as influenza A, SARS-CoV-2 and hRSV. Thus, while waning immunity contributes to reinfections with homologous viruses over time, viral escape is a mechanism that allows reinfections with heterologous viruses (Bull et al., 2025; Ranga and Asokan, 2021). Furthermore, waning immunity may promote immune escape by enabling variant strains to infect partially immune hosts, leading to the replacement of wild-type virus by escape mutants. Repeated antigen exposure enhances immune memory and affinity expanding the pool of memory T and B cells, thereby gradually reducing the risk of severe disease (Bull et al., 2025).

As with other mucosal surfaces, the respiratory tract is continuously exposed to particulate matter, environmental microbes, and commensal microbiota, promoting immune tolerance (Gollwitzer et al., 2014). This tolerogenic state may also contribute to the short-lived immune responses to respiratory viruses (Eddens et al., 2022). In addition, interactions with components of the microbiota may modulate the magnitude and duration of viral replication, thus limiting the development of long-lasting immune responses.

Upon exposure to respiratory antigens, tertiary lymphoid organs called inducible bronchus-associated lymphoid tissue (iBALT) may develop. These are located close to the basal side of the bronchial epithelium, in the perivascular space of pulmonary blood vessels, during inflammation. The cellular architecture of the iBALT is similar to secondary lymphoid organs, showing B cell follicles, germinal centers, and a T cell zone. Their protective role is mediated by a local source of cellular and humoral effectors (e.g., IgA and cytokines) that mediate local immunity and possibly avoid pathogen dissemination to other organs (Gao et al., 2023; Hwang et al., 2016). In infants and children, iBALT is found with increased frequency with respect to adults, likely due to initial exposure to a large repertoire of respiratory pathogens and allergens. However, iBALT can form across all age groups following a respiratory infection. Repeated antigen exposure seems necessary not only to promote iBALT formation but also to maintain persistence over time (Fig. 3) (Foo and Phipps, 2010; Hwang et al., 2016; Marin et al., 2019).

FIG. 3.

Factors involved in the immune response to hRSV. Respiratory mucosal infection and inflammation result in the formation of inducible bronchus-associated lymphoid tissue (iBALT), which serves as a local source of protective antibodies (IgA), B, and T lymphocytes. Repeated exposure to viral antigens induces the development of larger and more long-lasting iBALT structures, protection against respiratory pathogens. The lack of exposure to hRSV during the COVID-19 pandemic reduced antigen presentation and the maintenance of specific lymphocytes within iBALT. Maternal antibodies are also involved in protection against hRSV severe disease in infants <3 months old. High antibody titers are not enough to achieve reduced viral loads. Antibody avidity maturation correlates with viral neutralizing activity. Created with Biorender.

During the COVID-19 pandemic lockdown, circumvention of social interaction and the low-to-null exposure to respiratory viruses led to a decline in iBALT-mediated protection against hRSV in adults. Naïve infants and children, who had never formed iBALT, were deficient in this type of local immune structure, explaining at least partially the increased hRSV transmission and hospitalization rates (Hwang et al., 2016; Ranga and Asokan, 2021).

Conclusions

The observed reduction in hRSV-specific immunity and increased severity of this respiratory infection during the COVID-19 pandemic are multifactorial. Immunological and virological mechanisms contribute to higher viral transmission and differential pathogenesis in infants, adults, and immunocompromised individuals. Further studies are needed to explore the functional roles and interplay of anti-hRSV antibodies, virus-specific T cells and lymphoid structures such as iBALT in protection against severe disease and reinfection. Such studies could provide valuable insights into the nature of protective immune responses elicited during hRSV infection and elucidate the mechanisms to enhance local mucosal immunity.

Antibody titer alone does not appear to be directly associated with disease severity and hospitalization rates. Instead, the effectiveness of the humoral response is likely determined by the combination of antibody avidity, neutralizing capacity, and probably the antibody subclass, in addition to titer. The data also highlight the importance of sustained specific antibody production induced by continuous or repeated exposure to the virus, driving affinity maturation. From the viral perspective, the antigenic variability between hRSV subgroups A and B, as well as among the different viral lineages, highlights the need to study subgroup- and genotype-specific immune responses. Such studies may help understand how antigenic differences contribute to age-related disease severity, particularly in the context of altered exposure following the COVID-19 pandemic.

Footnotes

Acknowledgment

The authors thank Mayra Cruz-Rivera and Guadalupe Toledo Gómez for their support and comments.

Author Disclosure Statement

The authors declare no conflict of interest.

Funding Information

This work was supported by the Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI), Mexico, project CBF2023-2024-2356.

Authors’ Contributions

F.M. and E.R.-T. conducted the literature search, collected, organized, analyzed the data and wrote the manuscript. T.P., C.S.-O., G.A.-R., and A.F. reviewed and critically analyzed the literature contributing to the conceptual and analytical content of the manuscript.

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