Introduction
Respiratory syncytial virus (RSV) remains one of the most significant viral threats to infant respiratory health worldwide, causing severe lower respiratory tract infections that can lead to hospitalization and long-term pulmonary complications. Despite decades of research, effective and durable protective strategies for early life remain elusive, largely due to fundamental age-dependent differences in immune function. Infants exhibit distinct mucosal immune responses compared to adults, particularly at the level of antibody production and immune regulation. Understanding how these developmental differences influence susceptibility to RSV is critical for advancing vaccine development and improving clinical outcomes in this vulnerable population.
Age-Dependent Mucosal Immunity in RSV Infection
Mucosal immunity in the respiratory tract undergoes profound developmental changes from infancy to adulthood, shaping host defense against RSV. In infants, immune responses are biased toward tolerance and immune regulation, a feature thought to protect against excessive inflammation during early microbial exposure. However, this bias results in diminished antiviral effector responses, including reduced antibody production at mucosal surfaces. These age-specific immune characteristics contribute to higher viral replication, prolonged infection, and increased disease severity in infants compared to adults during RSV infection.
Role of IgA in Controlling RSV at Respiratory Surfaces
Immunoglobulin A (IgA) is the predominant antibody isotype at respiratory mucosal surfaces and serves as a first line of defense against RSV by neutralizing the virus and limiting epithelial infection. In adults, robust RSV-specific IgA responses correlate with reduced viral load and milder disease. In contrast, infants exhibit markedly reduced IgA production following RSV exposure. This deficiency compromises mucosal barrier protection and facilitates viral persistence, highlighting IgA as a critical but underdeveloped component of early-life immunity against RSV.
Impaired Class Switch Recombination in Infant B Cells
The failure of infants to generate strong IgA responses during RSV infection is closely linked to impaired class switch recombination (CSR) in B cells. Neonatal B cells display intrinsic limitations in undergoing CSR due to reduced expression of key activation-induced cytidine deaminase (AID) and altered signaling through cytokine and costimulatory pathways. These molecular constraints limit the diversification of antibody isotypes, skewing responses toward less effective humoral immunity and reinforcing susceptibility to severe RSV disease in early life.
Regulatory B Cells as Modulators of Antiviral Immunity
Regulatory B cells (Bregs), particularly neonatal Bregs (nBregs), have emerged as critical modulators of immune responses during infancy. These cells exert immunosuppressive effects through cytokine production, such as interleukin-10, dampening antiviral T-cell responses and inhibiting effective B-cell activation. During RSV infection, nBregs can suppress class switch recombination and IgA production, thereby limiting protective mucosal immunity. While this regulatory function may prevent immunopathology, it paradoxically contributes to increased viral burden and disease severity in infants.
Implications for Infant-Specific RSV Vaccine Design
Elucidating the mechanisms underlying impaired IgA responses and Breg-mediated immune suppression has profound implications for RSV vaccine development. Traditional vaccine strategies designed for adults may fail in infants due to their unique immune regulatory environment. Targeted approaches that enhance mucosal IgA production, modulate Breg activity, or promote age-appropriate B-cell maturation may offer more effective protection. A deeper understanding of infant-specific immune pathways is essential for the rational design of next-generation RSV vaccines and immunomodulatory interventions tailored to early life.
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