mRNA vaccination drives differential mucosal neutralizing antibody profiles in naïve and SARS-CoV-2 previously-infected individuals

Abstract

Two doses of BNT162b2 mRNA vaccine induces a strong systemic SARS-CoV-2 specific humoral response. However, SARS-CoV-2 airborne transmission makes mucosal immune response a crucial first line of defense. Therefore, we characterized SARS-CoV-2-specific IgG responses induced by BNT162b2 vaccine, as well as IgG responses to other pathogenic and seasonal human coronaviruses in oral fluid and plasma from 200 UK healthcare workers who were naïve (N=62) or previously infected with SARS-CoV-2 (N=138) using a pan-coronavirus multiplex binding immunoassay (Meso Scale Discovery®). Additionally, we investigated the impact of historical SARS-CoV-2 infection on vaccine-induced IgG, IgA and neutralizing responses in selected oral fluid samples before vaccination, after a first and second dose of BNT162b2, as well as following a third dose of mRNA vaccine or breakthrough infections using the same immunoassay and an ACE2 inhibition assay. Prior to vaccination, we found that spike-specific IgG levels in oral fluid positively correlated with IgG levels in plasma from previously-infected individuals (Spearman r=0.6858, p<0.0001) demonstrating that oral fluid could be used as a proxy for the presence of plasma SARS-CoV-2 IgG. However, the sensitivity was lower in oral fluid (0.85, 95% CI 0.77-0.91) than in plasma (0.94, 95% CI 0.88-0.97). Similar kinetics of mucosal and systemic spike-specific IgG levels were observed following vaccination in naïve and previously-infected individuals, respectively. In addition, a significant enhancement of OC43 and HKU1 spike-specific IgG levels was observed in previously-infected individuals following one vaccine dose in oral fluid (OC43 S: p<0.0001; HKU1 S: p=0.0423) suggesting cross-reactive IgG responses to seasonal beta coronaviruses. Mucosal spike-specific IgA responses were induced by mRNA vaccination particularly in previously-infected individuals (71%) but less frequently in naïve participants (23%). Neutralizing responses to SARS-CoV-2 ancestral and variants of concerns were detected following vaccination in naïve and previously-infected participants, with likely contribution from both IgG and IgA in previously-infected individuals (correlations between neutralizing responses and IgG: Spearman r=0.5642, p<0.0001; IgA: Spearman r=0.4545, p=0.0001). We also observed that breakthrough infections or a third vaccine dose enhanced mucosal antibody levels and neutralizing responses. These data contribute to show that a previous SARS-CoV-2 infection tailors the mucosal antibody profile induced by vaccination.

Omicron BA.1/BA.2 infections in triple-vaccinated individuals enhance a diverse repertoire of mucosal and blood immune responses

“…We found that spike-specific mucosal antibodies were low after the 3rd mRNA vaccine dose and similar between SARS-CoV-2 naive and previously-infected individuals. We and others have shown that mucosal IgA is induced by mRNA vaccines in those with a history of prior SARS-CoV-2 (23,24), so this finding was unexpected, and is perhaps explained by our cohort being enriched for previously-infected healthcare workers with low mucosal immunity and therefore at risk of breakthrough infection. We have also previously noted a waning of mucosal IgA over 9 months after SARS-CoV-2 infection (25) and the time to first infection in our previously-infected cohort was much longer.…”

Omicron infection following vaccination enhances a broad spectrum of immune responses dependent on infection history

“…We found that spike-specific mucosal antibodies were low after the 3rd mRNA vaccine dose and similar between SARS-CoV-2 naive and previously-infected individuals. We and others have shown that mucosal IgA is induced by mRNA vaccines in those with a history of prior SARS-CoV-2 24 , 25 , so this finding was unexpected and is perhaps explained by our selection of a cohort of healthcare workers who experienced an omicron infection, thereby potentially enriching for previously-infected individuals at increased risk of breakthrough infection due to low mucosal immunity. We have also previously noted a waning of mucosal IgA over 9 months after SARS-CoV-2 infection 26 and the time to first infection in our previously-infected cohort was much longer.…”

High SARS-CoV-2 incidence and asymptomatic fraction during Delta and Omicron BA.1 waves in The Gambia

“…Our Omicron BA.1 attack rate estimated by a combination of RT-PCR and serology is very similar to those based on serological modelling from urban (58%) and rural (65%) South Africa in the PHIRST-C cohorts 23 . Further exploration of immune correlates of protection in our cohort will be valuable, with a particular focus on mucosal immunity, which is induced by infection but less consistently by parenteral vaccines 24 , 25 .…”