7-month duration of SARS-CoV-2 mucosal immunoglobulin-A responses and protection.

Mucosal immunity has a pivotal role in protection from respiratory viral infections.1Focosi D Maggi F Casadevall A Mucosal vaccines, sterilizing immunity, and the future of SARS-CoV-2 virulence.Viruses. 2022; 14: 187Google Scholar The current authors have showed substantial protection from omicron infection by high concentrations of nasal mucosal SARS-CoV-2 WT spike immunoglobulin-A (M-IgA) over a 4-week screening period.2Havervall S Marking U Svensson J et al.Anti-spike mucosal IgA protection against SARS-CoV-2 omicron infection.N Engl J Med. 2022; 387: 1333-1336Google Scholar A sharp increase in M-IgA concentrations following BA.1 or BA.2 breakthrough infection in triple vaccinated health-care workers was also observed.2Havervall S Marking U Svensson J et al.Anti-spike mucosal IgA protection against SARS-CoV-2 omicron infection.N Engl J Med. 2022; 387: 1333-1336Google Scholar Here, we present follow-up data with prospectively collected omicron infection rates and systemic and mucosal antibody concentrations from the same cohort (appendix pp 7–9, 12–14). The association between M-IgA concentrations at the 75th percentile or higher at enrolment and a reduced risk of symptomatic BA.1, BA.2, or BA.5 breakthrough infection remained over an 8-month follow-up period, with a hazard ratio (HR) of 0·55 (95% CI 0·35–0·87), much due to the initial risk difference (figure A). Serum WT spike-specific IgG (S-IgG) concentrations waned over 8 months following a third vaccine dose in all study participants (appendix p 10), concurrent with previous data.3Gilboa M Regev-Yochay G Mandelboim M et al.Durability of immune response after COVID-19 booster vaccination and association with COVID-19 omicron infection.JAMA Netw Open. 2022; 5 (e2231778): e2231778Google Scholar However, concentrations of nasal M-IgA in participants with previous SARS-CoV-2 infection, but without omicron breakthrough infection, remained above the amount associated to 65% protection2Havervall S Marking U Svensson J et al.Anti-spike mucosal IgA protection against SARS-CoV-2 omicron infection.N Engl J Med. 2022; 387: 1333-1336Google Scholar over the 8-month study period (figure C). This finding suggests a long-lasting mucosal immunity evoked by SARS-CoV-2 infection. We next followed systemic and mucosal immune responses in participants that had a BA.1 or BA.2 breakthrough infection during the screening study. 7 months following breakthrough infection, S-IgG concentrations waned to be lower than at baseline (appendix p 10). As previously shown,4Blom K Marking U Havervall S et al.Immune responses after omicron infection in triple-vaccinated health-care workers with and without previous SARS-CoV-2 infection.Lancet Infect Dis. 2022; 22: 943-945Google Scholar serological responses were lower among participants with a history of SARS-CoV-2 infection before breakthrough infection compared with those without and the difference remained over the 7-months follow-up (appendix p 10). Whether these findings reflect immune imprinting after previous infection5Reynolds CJ Pade C Gibbons JM et al.Immune boosting by B.1.1.529 (omicron) depends on previous SARS-CoV-2 exposure.Science. 2022; 377eabq1841Google Scholar or a hampered systemic viral replication due to stronger and more rapid mucosal immune responses2Havervall S Marking U Svensson J et al.Anti-spike mucosal IgA protection against SARS-CoV-2 omicron infection.N Engl J Med. 2022; 387: 1333-1336Google Scholar needs further investigation. Interestingly, although nasal M-IgA concentrations waned, they remained above the protective threshold2Havervall S Marking U Svensson J et al.Anti-spike mucosal IgA protection against SARS-CoV-2 omicron infection.N Engl J Med. 2022; 387: 1333-1336Google Scholar in 94% of participants with previous SARS-CoV-2 WT or delta infection and in 58% of previously SARS-CoV-2-naive participants (figure B). In line with this, and in agreement with recent population-based data,6Malato J Ribeiro RM Leite PP et al.Risk of BA.5 infection among persons exposed to previous SARS-CoV-2 variants.N Engl J Med. 2022; 387: 953-954Google Scholar, 7Altarawneh HN Chemaitelly H Ayoub HH et al.Protective effect of previous SARS-CoV-2 infection against omicron BA.4 and BA.5 subvariants.N Engl J Med. 2022; 387: 1620-1622Google Scholar BA.1 and BA.2 infections were strongly protective against subsequent BA.5 infection in this cohort, with a HR of 0·13 (95% CI 0·04–0·44; figure D). To assess whether M-IgA in nasal samples originated in the mucosa, we correlated M-IgA to mucosal spike-specific secretory IgA in nasal samples, and M-IgA to spike-specific IgA in serum. Concentrations of M-IgA correlated stronger to mucosal secretory IgA in nasal samples (r=0·9, p<0·001) than to spike-specific IgA in serum (r=0·64, p<0·001) (appendix p 11). Although a spillover from the circulation cannot be ruled out, these results indicate a mucosal origin of nasal IgA. These findings highlight the key role of antigen presentation at the mucosa and support a protective effect of mucosal immunity for up to 8 months. Whether nasal or oral vaccines can elicit mucosal immune responses and protection similar to those following natural infection in mRNA-vaccinated individuals, will be an important aspect of ongoing clinical trials. We declare no competing interests. Download .pdf (1.06 MB) Help with pdf files Supplementary appendix