tetano
Editor, Senior Moderator
EBioMedicine
. 2026 Jun 30:129:106359.
doi: 10.1016/j.ebiom.2026.106359. Online ahead of print.
The role of mucosal IgA in protection against influenza A H1N1 virus infection in a real-world setting
Oscar Bladh[SUP] 1 [/SUP], Tamás Pongrácz[SUP] 1 [/SUP], Katherina Aguilera[SUP] 1 [/SUP], Matilda Berkell[SUP] 2 [/SUP], Ulrika Marking[SUP] 3 [/SUP], Nina Greilert Norin[SUP] 1 [/SUP], Ali Rihani[SUP] 4 [/SUP], Jessica J Alm[SUP] 5 [/SUP], Florian Krammer[SUP] 6 [/SUP], Mikael Åberg[SUP] 7 [/SUP], Charlotte Thålin[SUP] 8 [/SUP]
Affiliations
Background: Parenteral vaccines against influenza virus prevent severe disease but provide limited protection against infection, likely due to limited induction of mucosal immunity. However, direct clinical evidence for mucosal antibody-mediated protection against influenza virus infection in humans has been lacking. The aim of this study was to evaluate the role of antigen-specific mucosal IgA as a correlate of protection against influenza virus infection. We investigated H1-specific nasal IgA and serum IgG and the effect on influenza virus infection, with corresponding SARS-CoV-2 data from the same cohort as an internal comparator.
Methods: Using a prospective cohort study design, we analysed paired antigen-specific serum IgG and nasal IgA responses at baseline, after influenza A (H1N1) virus and SARS-CoV-2 infections, and after intramuscular influenza and SARS-CoV-2 vaccination. We then evaluated associations between baseline antibody levels, vaccination, and the risk of subsequent influenza A (H1N1) virus infection or SARS-CoV-2 infections in a 4-month home-based qPCR screening in Stockholm, Sweden (2023-2024). A Poisson regression model with a log offset for time at risk was used to evaluate if baseline antigen-specific nasal IgA or serum IgG levels or recent vaccination was associated with protection against infection. Antibody quantification was performed using a highly sensitive electrochemiluminescence immunoassay (Meso Scale Diagnostics, USA) optimised for mucosal sampling.
Findings: A total of 926 study participants were enrolled. After influenza A (H1N1) virus infection, H1-specific nasal IgA and serum IgG increased (p = 0.007 and p < 0.001 respectively), while vaccination boosted serum IgG (p = 0.006) but not nasal IgA. Baseline nasal H1-specific IgA were lower in H1N1-infected individuals (p = 0.024), and notably, baseline nasal H1-specific IgA above median was associated with reduced H1N1 infection risk (IRR 0.23, 95% CI 0.05-0.75, p = 0.026), while serum IgG and recent vaccination were not (IRR 2.03, 0.70-6.62, p = 0.206 and IRR 1.06, 0.38-3.03, p = 0.917, respectively). Moreover, each two-fold increase in baseline nasal H1-specific IgA levels was associated with a significantly lower infection risk (IRR 0.69, 95% CI 0.51-0.92; p = 0.014). Similar findings were observed for SARS-CoV-2 for mucosal IgA, whereas baseline serum spike-specific IgG above the median was also associated with reduced risk of infection.
Interpretation: Leveraging fit-for-purpose sampling, a validated and highly sensitive assay, and a large real-world cohort, we directly link mucosal IgA to protection against influenza virus infection. While currently employed vaccines provide robust protection against severe disease and hospital admissions, these findings highlight the need for novel approaches generating robust mucosal protection against infection per se, and the need to incorporate mucosal endpoints into next-generation vaccine development aiming for infection-blocking immunity.
Funding: This work was funded by the European Research Council (101164772 - D-MAP), the Swedish Society for Medical Research (SSMF CG-24-0191-B-H-01), the Knut and Alice Wallenberg Foundation (KAW 2024.0108), and the SciLifeLab Pandemic Laboratory Preparedness Program.
Keywords: Correlate of protection; Infection; Influenza A; Mucosal antibodies; SARS-CoV-2; Vaccines.
. 2026 Jun 30:129:106359.
doi: 10.1016/j.ebiom.2026.106359. Online ahead of print.
The role of mucosal IgA in protection against influenza A H1N1 virus infection in a real-world setting
Oscar Bladh[SUP] 1 [/SUP], Tamás Pongrácz[SUP] 1 [/SUP], Katherina Aguilera[SUP] 1 [/SUP], Matilda Berkell[SUP] 2 [/SUP], Ulrika Marking[SUP] 3 [/SUP], Nina Greilert Norin[SUP] 1 [/SUP], Ali Rihani[SUP] 4 [/SUP], Jessica J Alm[SUP] 5 [/SUP], Florian Krammer[SUP] 6 [/SUP], Mikael Åberg[SUP] 7 [/SUP], Charlotte Thålin[SUP] 8 [/SUP]
Affiliations
- PMID: 42378965
- DOI: 10.1016/j.ebiom.2026.106359
Background: Parenteral vaccines against influenza virus prevent severe disease but provide limited protection against infection, likely due to limited induction of mucosal immunity. However, direct clinical evidence for mucosal antibody-mediated protection against influenza virus infection in humans has been lacking. The aim of this study was to evaluate the role of antigen-specific mucosal IgA as a correlate of protection against influenza virus infection. We investigated H1-specific nasal IgA and serum IgG and the effect on influenza virus infection, with corresponding SARS-CoV-2 data from the same cohort as an internal comparator.
Methods: Using a prospective cohort study design, we analysed paired antigen-specific serum IgG and nasal IgA responses at baseline, after influenza A (H1N1) virus and SARS-CoV-2 infections, and after intramuscular influenza and SARS-CoV-2 vaccination. We then evaluated associations between baseline antibody levels, vaccination, and the risk of subsequent influenza A (H1N1) virus infection or SARS-CoV-2 infections in a 4-month home-based qPCR screening in Stockholm, Sweden (2023-2024). A Poisson regression model with a log offset for time at risk was used to evaluate if baseline antigen-specific nasal IgA or serum IgG levels or recent vaccination was associated with protection against infection. Antibody quantification was performed using a highly sensitive electrochemiluminescence immunoassay (Meso Scale Diagnostics, USA) optimised for mucosal sampling.
Findings: A total of 926 study participants were enrolled. After influenza A (H1N1) virus infection, H1-specific nasal IgA and serum IgG increased (p = 0.007 and p < 0.001 respectively), while vaccination boosted serum IgG (p = 0.006) but not nasal IgA. Baseline nasal H1-specific IgA were lower in H1N1-infected individuals (p = 0.024), and notably, baseline nasal H1-specific IgA above median was associated with reduced H1N1 infection risk (IRR 0.23, 95% CI 0.05-0.75, p = 0.026), while serum IgG and recent vaccination were not (IRR 2.03, 0.70-6.62, p = 0.206 and IRR 1.06, 0.38-3.03, p = 0.917, respectively). Moreover, each two-fold increase in baseline nasal H1-specific IgA levels was associated with a significantly lower infection risk (IRR 0.69, 95% CI 0.51-0.92; p = 0.014). Similar findings were observed for SARS-CoV-2 for mucosal IgA, whereas baseline serum spike-specific IgG above the median was also associated with reduced risk of infection.
Interpretation: Leveraging fit-for-purpose sampling, a validated and highly sensitive assay, and a large real-world cohort, we directly link mucosal IgA to protection against influenza virus infection. While currently employed vaccines provide robust protection against severe disease and hospital admissions, these findings highlight the need for novel approaches generating robust mucosal protection against infection per se, and the need to incorporate mucosal endpoints into next-generation vaccine development aiming for infection-blocking immunity.
Funding: This work was funded by the European Research Council (101164772 - D-MAP), the Swedish Society for Medical Research (SSMF CG-24-0191-B-H-01), the Knut and Alice Wallenberg Foundation (KAW 2024.0108), and the SciLifeLab Pandemic Laboratory Preparedness Program.
Keywords: Correlate of protection; Infection; Influenza A; Mucosal antibodies; SARS-CoV-2; Vaccines.