SARS-CoV-2 convalescence and hybrid immunity elicits mucosal immune responses

Abstract

Background: Mucosal antibodies play a key role in the protection against SARS-CoV-2 infection in the upper respiratory tract, and potentially in limiting virus replication and therefore onward transmission. While systemic immunity to SARS-CoV-2 is well understood, we have a limited understanding about the antibodies present on the nasal mucosal surfaces.

Methods: In this study, we evaluated SARS-CoV-2 mucosal antibodies following previous infection, vaccination, or a combination of both. Paired nasal fluid and serum samples were collected from 143 individuals, which include convalescent, vaccinated, or breakthrough infections.

Findings: We detected a high correlation between IgG responses in serum and nasal fluids, which were higher in both compartments in vaccinated compared to convalescent participants. Contrary, nasal and systemic SARS-CoV-2 IgA responses were weakly correlated, indicating a compartmentalization between the local and systemic IgA responses. SARS-CoV-2 secretory component IgA (s-IgA) antibodies, present exclusively on mucosal surfaces, were detected in the nasal fluid only in a minority of vaccinated subjects and were significantly higher in previously infected individuals. Depletion of IgA antibodies in nasal fluids resulted in a tremendous reduction of neutralization activity against SARS-CoV-2, indicating that IgA is the crucial contributor to neutralization in the nasal mucosa. Neutralization against SARS-CoV-2 was higher in the mucosa of subjects with previous SARS-CoV-2 infections compared to vaccinated participants.

Interpretation: In summary, we demonstrate that currently available vaccines elicit strong systemic antibody responses, but SARS-CoV-2 infection generates higher titers of binding and neutralizing mucosal antibodies. Our results support the importance to develop SARS-CoV-2 vaccines that elicit mucosal antibodies.

Funding: The work was funded by the COVID-19 National Research Program 78 (grant number 198412) of the Swiss National Science Foundation.

Keywords: COVID-19; Mucosal immunity; SARS-CoV-2; Secretory IgA.

Fig. 1

Correlation of SARS-CoV-2 IgA and IgG antibody responses in NLF and serum. Correlation between anti-triS serum and NLF IgA (a) and IgG (b) antibody titers (log₁₀ ng/mL) of samples collected from convalescent, vaccinated and subjects with hybrid immunity. NLF triS IgA titers normalized to the levels of total IgA from the same sample. Spearman rank correlation coefficient and p values are shown.

Fig. 2

Mucosal and serum antibody responses in subjects with previous infection compared to vaccinated only. (a and b) Anti-triS IgA (log₁₀ ng/mL) measured in NLF (a) and serum (b) of vaccinated with 2 or 3 doses, or convalescent. (c) Anti-triS s-IgA (log₁₀ AU/mL) antibody titers in NLF of vaccinated with 2 or 3 doses, or convalescent. (d and e) Anti-triS IgG (log₁₀ ng/mL) measured in NLF (d) and serum (e) of vaccinated with 2 or 3 doses, or convalescent. A generalized linear model was used to determine differences of means, p values are shown above brackets. The mean + 3SD of 11 negative samples was used to set a cut-off for anti-triS IgA, s-IgA and IgG in NLF. The mean + 3SD of 56 pre-pandemic serum samples was used to set a cut-off for anti-triS IgA in serum samples. The mean + 3SD of 48 pre-pandemic serum samples was used to set a cut-off for anti-triS IgG in serum samples.

Fig. 3

Mucosal and serum antibody responses in convalescent compared to subjects with hybrid immunity. (a and b) Anti-triS IgA (log₁₀ ng/mL) measured in NLF (a) and serum (b) of convalescent or subjects with hybrid immunity. (c) Anti-triS s-IgA (log₁₀ AU/mL) antibody titers in NLF of convalescent or subjects with hybrid immunity. (d and e) Anti-triS IgG measured in NLF (d) and serum (e) of convalescent or subjects with hybrid immunity. A generalized linear model was used to determine differences of means, p values are shown above brackets. The mean + 3SD of 11 negative samples was used to set a cut-off for anti-triS IgA, s-IgA and IgG in NLF. The mean + 3SD of 56 pre-pandemic serum samples was used to set a cut-off for anti-triS IgA in serum samples. The mean + 3SD of 48 pre-pandemic serum samples was used to set a cut-off for anti-triS IgG in serum samples.

Fig. 4

Neutralizing antibody responses in the nasal mucosae of vaccinated and subjects with hybrid immunity. (a) Each dot represents the neutralizing titer (FRNT₅₀) of an individual NLF sample against SARS-CoV-2 ancestral (a) and Omicron BA.5 variant (b). (c) IgA antibodies were purified from the NLFs, each symbol represents the same subject. Neutralizing titers against ancestral SARS-CoV-2 measured from different fractions are displayed. The generalized linear model was used to determine differences of means, p values are shown above brackets.