Evaluation of a Respiratory Syncytial Virus Subunit Vaccine Candidate in IgA-Deficient Mice: Insights into the Role of IgA in Vaccine-Induced Immunity and Protection.

BACKGROUND/

OBJECTIVES

Respiratory Syncytial Virus (RSV) causes severe disease in infants, the elderly, and immunocompromised individuals, with reinfections linked to poor induction of durable mucosal immunoglobulin A (IgA). We investigated the role of IgA in immunity and protection induced by a RSV subunit vaccine candidate, tFrsc/TriAdj, which consists of a truncated RSV fusion protein (tFrsc) with a tri-component adjuvant (TriAdj).

METHODS

Wild-type (IgA+/+) and IgA-deficient (IgA-/-) BALB/c mice were immunized intranasally and subsequently challenged with RSV.

RESULTS

Vaccination with tFrsc/TriAdj induced robust systemic and mucosal IgG, and high lung and serum neutralizing antibodies, in both IgA+/+ and IgA-/- mice. As expected, IgA-/- mice lacked IgA and exhibited modest reductions in nasal IgG compared to IgA+/+ mice following challenge, correlating to failure to clear RSV from the upper respiratory tract. In contrast, viral replication in the lungs was fully suppressed in both genotypes, indicating that IgG alone was sufficient for lower respiratory tract protection. Isotype analysis revealed diminished Th1-associated IgG2a and elevated IgG1 across mucosal and systemic compartments in IgA-/- mice, suggesting a Th2 bias. Flow cytometric analysis confirmed reduced recruitment of IFN-γ+ CD4+ T cells in the lungs of immunized IgA-/- mice. Interestingly, IL-17 production and numbers of IL-17+ CD4+ T cells in the lungs were increased, suggesting an enhanced Th17 response. Furthermore, IgA-deficient mice displayed reduced splenic IgG+ B cell populations, which is also a novel observation.

CONCLUSIONS

Collectively, these findings demonstrate that although tFrsc/TriAdj confers lower airway protection in the absence of IgA, vaccine-induced IgA is critical for upper airway protection, Th1/balanced immune responses, and optimal B cell responses.