Current COVID-19 intramuscular vaccination strategies stimulate good systemic responses that protect against severe disease, however, recurring breakthrough infections highlight the marked ability of SARS-CoV-2 variants of concern, especially Omicron, to escape neutralization. Furthermore, recent studies have observed limited mucosal immunity in COVID-vaccinated individuals, thus contributing to their increased susceptibility to Omicron variants. Here, we examined whether hybrid immunity following breakthrough infections may provide more robust systemic, and more importantly, mucosal humoral immunity to emerging SARS-CoV-2 variants.
A series of longitudinal paired mucosal (saliva) and systemic (plasma) samples were collected from individuals during the acute phase of Delta, Omicron BA.1 and BA.2 breakthrough infections. We profiled these samples for their SARS-CoV-2 variant-specific (Ancestral, Delta, Omicron BA.1, BA.2) antibody isotype responses (IgG, IgA) and their ability to mediate Fc-effector functions via engaging Fc-receptors.
Following Delta breakthrough infection, a surge in Delta-specific mucosal IgG (+4000%; p<0.01) mucosal were observed two weeks post-infection, mimicking the increase in plasma responses (+1800%; p<0.01). Conversely, smaller non-significant peaks in Omicron BA.1 (+330%) and BA.2 (+523%) IgG salivary responses were observed two weeks into their respective breakthrough infections. This disparity is also reflected in the enhanced ability of Delta-specific salivary antibodies to engage Fc-receptors (+1595%; p<0.01) as compared to the weak non-significant changes in Omicron-specific salivary Fc-responses following their respective breakthrough infections.
Furthermore, unlike the robust Delta-specific salivary IgA response (+709%; p<0.01) following Delta breakthroughs, only modest rises in BA.1-specific (+30%; p=0.01) and BA.2-specific (+80%; p<0.01) mucosal IgA responses were observed following the respective Omicron breakthroughs. These Omicron-specific IgA responses were several folds lower as compared to that raised against the ancestral spike (BA.1: 12-fold less; BA.2: 5-fold less), suggesting immune imprinting of ancestral spike.
Our findings suggest that acquiring a single Omicron breakthrough infection might not be sufficient in priming mucosal immunity against future Omicron infections and supports the case for mucosal vaccines and Omicron-specific boosters to better protect vulnerable populations.