XBB 1.5 monovalent booster vaccination stimulates oral mucosal and systemic immune responses in healthy adults

The FDA approved the first monovalent XBB1.5 booster vaccine in September 2023. However, whether this vaccine stimulates mucosal immune responses in the oropharynx, especially neutralizing antibodies, remains understudied. We analyzed serum and saliva samples from 28 participants, collected one week before and two to three weeks after the XBB1.5 mRNA vaccination, for neutralizing and binding antibodies to Wuhan and XBB1.5 Spike (S) protein. We observed a 2.9-fold increase in Wuhan and a 5.0-fold rise in XBB1.5 serum neutralization titers after mRNA vaccination, which correlated with increased binding antibody levels against the S protein variants in serum. We also examined saliva to assess oral mucosal immune responses to vaccination. Vaccination caused a 1.7-fold increase in ACE2 neutralization in saliva against XBB1.5 ( p < 0.0001) and a 1.4-fold increase against Wuhan ( p = 0.03). This rise in neutralizing antibody levels in saliva was not associated with the number and timing of previous COVID-19 infections, vaccination status, vaccine type, age, sex, or increases in S-specific IgG in either saliva or serum. Individuals with the largest increase in XBB1.5 neutralization in saliva tended to show a greater rise in S-specific sIgA levels. Depletion of salivary IgA1 or IgG after vaccination revealed that IgA1 was mainly responsible for the increase in ACE2 blocking activity (average reduction in blocking activity with IgA1 depletion = 68%, range 58–81%) compared to IgG (average reduction = 27%, range 0–71%). The XBB1.5 monovalent vaccine boosts neutralizing antibody levels in blood and mucous membranes, with the largest increase observed against the XBB1.5 variant. This likely reflects the enhancement of cross-reactive antibodies influenced by prior exposure and hybrid immunity, rather than the production of entirely XBB1.5-specific responses. Improved oral mucosal immune responses may reduce the risk of COVID-19 infection and severe illness.