Nasal Mucosal Defenses Wanes 9 Months After SARS-CoV-2 Infection

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A new study led by researchers from Imperial College London-UK has found that UK SARS-CoV-2-specific nasal immunoglobin A or IgA wanes 9 months after hospitalization or infections with COVID-19 and is not induced by subsequent COVID-19 shots or boosters.

The study findings were published in the peer reviewed journal: eBioMedicine (Lancet)
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00584-9/fulltext

We demonstrate durable nasal and plasma IgG responses to ancestral (B.1 lineage), Delta and Omicron variants of SARS-CoV-2 in 446 adults hospitalised with COVID-19, who were infected with pre-Omicron virus and the majority of whom were subsequently vaccinated.

However, we found that nasal virus-specific IgA levels fell back to pre-COVID levels after 9 months and Omicron-binding nasal responses were particularly short-lived. Our results suggest that nasal IgA responses are compartmentalised from systemic responses after vaccination, which boosted nasal and plasma IgG but had limited effects on nasal IgA.

The durability of nasal antibody responses has hitherto been unclear. Whilst a Dutch study of healthcare workers found that nasal antibody lasted 9 months after mild infection, others demonstrated rapid waning after 3 months.8,9

Neither study examined a large cohort of hospitalised patients, and our findings confirm that COVID-19 can induce durable mucosal immunity. We also found that sex, disease severity and age did not impact the longevity of the nasal responses in keeping with a recent study of 26 unvaccinated individuals.10

By calibrating nasal antibody levels with pre-COVID samples, we demonstrate that on average, nasal IgA responses disappear after 9 months and Omicron-binding IgA is particularly short-lived. Nasal IgA is the most abundant mucosal antibody and provides an important first-line defence against respiratory infection.

The importance of nasal IgA in mediating immunity to SARS-CoV-2 is highlighted by a recent study where nasal IgA but not IgG correlates with nasal neutralisation after COVID-19.10 The short-lived nasal IgA response demonstrated here may explain the high rates of infection with Omicron variant, despite vaccination, and are in-keeping with real-world data showing that infection with pre-Omicron virus has minimal influence on the risk of Omicron infection at 15 months.15,29

Whilst we found that i.m. vaccination can boost nasal IgG, our data suggest it has limited effects on IgA, in keeping with a previous study of salivary antibody in 107 care home residents.30 We demonstrated correlations between nasal IgG, plasma IgG and plasma neutralisation, whilst nasal IgA responses were compartmentalised, suggesting that the rise in nasal IgG after vaccination could derive from plasma.

Notably, we demonstrate that those exhibiting stronger nasal IgA responses relative to plasma had been recently vaccinated. Although this analysis was limited by small sample size, our findings suggest that vaccination only transiently boosts nasal IgA. We did not observe differences in nasal IgA responses according to the type of vaccination received.

mRNA vaccines tend to induce stronger circulating antibody responses than those using adenoviral vectors, but our results suggest this may not apply to nasal responses.31,32

Taken together, these findings suggest that i.m. vaccination after COVID-19 is unlikely to recall mucosal responses.
The concept of independent mucosal and systemic immunity is supported by recent studies showing that SARS-CoV-2 naïve individuals (whose mucosa have not been primed) do not produce nasal IgA after i.m. vaccination, highlighting that an independent response must occur at mucosal sites.9,33

Moreover, previous work has demonstrated that transudation of plasma antibody makes minimal contribution to total antibody concentrations in the mucosa, even in cases of paraproteinaemia where plasma concentrations are extremely high.34

This would explain why i.m. vaccination has had only transient effects on transmission,4 which may be mediated by transiently enhanced nasal IgG responses, which we demonstrate after vaccination.

Given that monomeric IgG does not efficiently neutralise virus in the mucosa, it is unlikely that boosting this response will have considerable impact on mucosal susceptibility to infection.6,10 Future vaccines will need to substantially boost nasal IgA if they are to fully prevent infection and transmission.

To date, intranasal and aerosolized vaccines have shown the most promise in doing so.18,33,35 It is therefore essential to prioritise development of mucosal vaccines which can provide better protection against respiratory infections.

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