SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

Abstract

Background: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.

Methods: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.

Findings: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination.

Interpretation: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.

Funding: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript.

Keywords: COVID-19; Convalescent; Mucosal immunity; Nasal antibody; SARS-CoV-2 immunity; SARS-CoV-2 variants; Vaccination.

Fig. 1

Nasal and plasma antibody responses 12 months after infection. Nasal (A,B) and plasma (C,D) IgA and IgG responses to S of ancestral SARS-CoV-2 from 446 COVID-19 patients, compared to 25 pre-pandemic control samples (grey). Nasal (E,F) and plasma (G,H) IgA and IgG responses to NP of ancestral SARS-CoV-2. Nasal virus-specific antibody titres were normalised to total IgA or IgG concentration. Blue and red lines indicate the trajectory of median titres across timepoints. The horizontal dashed line indicates the threshold for positivity determined by the mean+2SD of controls. ∗ = p < 0.05, ∗∗ = p < 0.01, ∗∗∗ = p < 0.001, ∗∗∗∗ = p < 0.0001.

Fig. 2

Nasal and plasma antibody trajectories in vaccinated individuals. Trajectory of nasal IgA and IgG responses from 120 COVID-19 patients before and after first vaccination (A–B). Plasma IgA and IgG responses from 323 COVID-19 patients before and after first vaccination (C–D). Trajectories were modelled using a LOESS regression curve and 95% confidence intervals are shown in grey. The vertical dotted line indicates the time of first vaccination. The horizontal dashed line indicates the threshold for positivity determined by the mean+2SD of controls.

Fig. 3

Nasal and plasma antibody responses to variants of concern 12 months after infection. Nasal IgA (A–C), nasal IgG (D–G) and plasma IgG (G–I) responses to RBD of ancestral SARS-CoV-2, Delta, and Omicron (BA.1) variants in 446 COVID-19 patients compared to 25 pre-pandemic control samples (grey). Nasal virus-specific antibody titres were normalised to total IgA or IgG concentration. The horizontal dashed line indicates the threshold for positivity determined by the mean+2SD of controls. ∗ = p < 0.05, ∗∗ = p < 0.01, ∗∗∗ = p < 0.001, ∗∗∗∗ = p < 0.0001.

Fig. 4

Relationship between nasal and plasma antibody responses at 6 and 12 months. A) Correlogram of nasal and plasma IgA and IgG responses to S and NP, disease severity and age at 6 months (n = 62), when 48 of 52 individuals with known vaccination status had received their first vaccination and B) correlogram at 12 months (n = 112), when 103 of 108 individuals with known vaccination status had been vaccinated. All statistically significant correlations (p < 0.05) are denoted with ∗. The variables were hierarchically clustered. C) Heatmap of nasal IgA, plasma IgA and plasma IgG responses to S and RBD at 12 months (n = 112). Rows are annotated with vaccination status, age and disease severity according to the WHO clinical progression score: 3–4 = no continuous supplemental oxygen needed; 5 = continuous supplemental oxygen only; 6 = continuous/bi-level positive airway pressure ventilation or high-flow nasal oxygen; 7–9 = invasive mechanical ventilation or other organ support.