For the editor:
Mucosal IgA can provide immunity against respiratory viruses.1 Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulates mucosal IgA responses,2 and neutralizing IgA, including neutralizing IgA against the B.1.1.529 (omicron) variant of SARS-CoV-2, have been detected after infection with wild-type SARS-CoV-2.3 However, the potential role of mucosal IgA in protecting against SARS-CoV-2 infection is still largely unknown.
Panel A shows the screening and follow-up of healthcare workers in this study. Participants were selected by polymerase chain reaction (PCR) testing of nasal, oropharyngeal and salivary swab samples twice a week for 4 weeks. Mucosal antibody levels were determined from nasal swab specimens obtained at baseline (defined as 5 weeks post-booster dose) in all participants, as well as during and after subsequent omicron infection breakthroughs ( 57 attendees). Panel B shows wild-type (WT) tip-specific mucosal IgA levels at baseline. The thick horizontal bars indicate the median and the thin horizontal bars the 25th and 75th percentiles. (For participants with no prior infection, the median and 25th percentile were both 0.1 arbitrary units [AU] per milliliter.) Participants who were PCR-positive for SARS-CoV-2 at baseline are not included in the plot. Panel C shows the relative risk of infection by omicron and the difference in viral replication (measured as the nadir cycle threshold [Ct]) among participants with elevated levels of WT peak-specific mucosal IgA or IgG (defined as those at ≥75th percentile) at baseline compared to participants with lower levels (<75th percentile). Error bars indicate the 97.5% confidence interval. Panel D shows the median WT and omicron BA.1 subline of spike-specific mucosal IgA responses after breakthrough omicron infection.
We assessed SARS-CoV-2-specific mucosal antibody responses in 338 triple-vaccinated healthcare workers (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) at the time of enrollment. in a 4 week quantitative polymerase chain reaction screening study in January and February 2022.4 Mucosal antibody responses were then assessed over time in 57 participants who were infected with the omicron variant during the screening period (Figure 1A). Mucosal IgA and IgG responses were analyzed against previously obtained serological and viral data.4
Wild-type SARS-CoV-2 spike-specific mucosal IgA and IgG were detected in 210 participants (62%) and 337 participants (>99%), respectively (Fig. S1A and S1B). Spike-specific mucosal IgA levels (Figure 1B) but not IgG (Fig. S1C) were higher in participants with prior SARS-CoV-2 infection than in those without prior infection (P < 0.001). Primary vaccination schedule, time from third vaccine dose to time of sampling, age, and sex did not significantly affect wild-type spike-specific mucosal IgA levels (Table S2).
Next, we assessed the potential protective effects of mucosal antibodies against omicron infection and viral replication. Participants who had elevated levels of wild-type peak-specific mucosal IgA (defined as those at ≥75th percentile) at enrollment had a significantly lower risk of subsequent infection with omicron than those whose levels were lower (relative risk, 0.35; 97.5% confidence interval [CI]0.11 to 0.91) (Figure 1C and Table S3); this effect was not found among participants who had elevated IgG levels at enrollment. Results were similar among participants with and without prior infection (Fig. S2 and Table S4). At baseline, omicron BA.1 subline tip-specific mucosal IgA levels were generally lower than wild-type tip-specific mucosal IgA levels (Fig. S1). However, a slightly but not significantly lower risk of subsequent omicron infection was noted in participants with high levels of peak BA.1 mucosal-specific IgA at baseline than in those with low levels at baseline ( relative risk, 0.63; 97.5% CI, 0.22 to 1.49). We also observed non-significantly lower levels of viral replication in infected participants who had elevated baseline levels of wild-type peak specific mucosal IgA (difference in nadir cycle threshold value, 3.91; 97 CI .5%, -0.87 to 8.70) (Figure 1C and table S5); this effect was not found in participants who had high baseline levels of IgG.
We analyzed the kinetics of mucosal antibody responses after breakthrough infection with omicron. Levels of spike-specific, receptor-binding domain-specific, and nucleocapsid-specific mucosal IgA increased over time after infection in both previously infected and previously uninfected participants (Figure 1D and Figure S3). This finding contrasts with the results of recent studies by our group.4 and Reynolds et al.,5 which showed omicron-induced stimulation of spike-specific systemic IgG responses, primarily in participants who had not been previously infected. Wild-type spike-specific mucosal IgA levels did not correlate with wild-type spike-specific mucosal or serum IgG levels (Fig. S4A and S4B). However, a strong correlation was observed between spike-specific serum and mucosal IgG levels (Spearman’s r=0.7, P<0.001) (Fig. S4C), a finding that supports a “spillover” of 'IgG from the circulation to the mucosa.1
Taken together, these results suggest that the tip-specific mucosal IgA of wild-type SARS-CoV-2 protects against omicron infection. Further studies are warranted to determine whether vaccines that induce a combination of mucosal and systemic immune responses would confer stronger protection than intramuscular vaccines.
Sebastien Havevall, MD
Ulrika Marking, MD
Julia Svensson, M.Sc.
Nina Greilert-Norin, RN
Karolinska Institute, Stockholm, Sweden
Philip Bacchus, M.Sc.
Swedish Armed Forces, Umeå, Sweden
Peter Nilsson, Ph.D.
Sophia Hober, Ph.D.
KTH Royal Institute of Technology, Stockholm, Sweden
Max Gordon, MD, Ph.D.
Karolinska Institute, Stockholm, Sweden
Kim Blom, Ph.D.
Jonas Klingstrom, Ph.D.
Swedish Public Health Agency, Solna, Sweden
Mikael Åberg, Ph.D.
Uppsala University, Uppsala, Sweden
Anna Smed-Sörensen, Ph.D.
Charlotte Thalin, MD, Ph.D.
Karolinska Institute, Stockholm, Sweden
Supported by grants from the Jonas and Christina af Jocknick Foundation (to Dr Thålin), Region of Stockholm (to Dr Thålin), Knut and Alice Wallenberg Foundation (to Drs Thålin, Åberg and Klingström), Foundation of the Leif Lundblad family (to Dr Thålin), the Swedish Research Council (to Dr Smed-Sörensen), the Swedish Heart and Lung Foundation (to Dr Smed-Sörensen), the Bill and Melinda Gates Foundation (to Dr Smed -Sörensen), and the Center for Innovative Medicine (to Drs Blom and Klingström).
The disclosure forms provided by the authors are available with the full text of this letter on NEJM.org.
This letter was published on September 14, 2022 on NEJM.org.
Drs. Havervall, Marking, Klingström, Åberg, Smed-Sörensen and Thålin also contributed to this letter.
1. fiery D, Maggi F, Casadevall A. Mucosal vaccines, sterilizing immunity and the future of SARS-CoV-2 virulence. Virus 2022;14:187–187.
2. Cagigi A, Yum, Osterberg B, et al. Respiratory tract antibodies emerge depending on the severity of COVID-19 and decline rapidly but reappear after SARS-CoV-2 vaccination. JCI Overview 2021;6(22):e151463–e151463.
3. Board C, Fernandez I, Bruel T, et al. Potent human IgA and IgG antibodies broadly neutralizing SARS-CoV-2, effective against omicron BA.1 and BA.2. J Med Exp 2022;219(7):e20220638–e20220638.
4. Blom K, U-mark, Haveval S, et al. Immune responses after omicron infection in triply vaccinated healthcare workers with and without prior SARS-CoV-2 infection. Lancet Infect Dis 2022;22:943–945.
5. CJ Reynolds, Pade C, JM Gibbons, et al. Immune enhancement by B.1.1.529 (omicron) depends on prior exposure to SARS-CoV-2. Science 2022;377(6603):eabq1841–eabq1841.
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