# 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

## TL;DR

This study shows that IgA is crucial for upper airway protection and balanced immune responses after RSV vaccination, even though lower airway protection can occur without it.

## Contribution

The study reveals the specific role of IgA in vaccine-induced immunity and protection against RSV, particularly in mucosal and systemic immune responses.

## Key findings

- IgA-deficient mice failed to clear RSV from the upper respiratory tract despite high lung and serum neutralizing antibodies.
- IgA deficiency led to a Th2 bias and reduced Th1-associated IgG2a, with increased Th17 responses in the lungs.
- IgA-deficient mice had reduced splenic IgG+ B cell populations, a novel observation.

## Abstract

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.