Future COVID-19 control will require vaccines that induce better mucosal immunity

In a recent study posted to the medRxiv* preprint server, researchers in France explored the relationship between long-term immunoglobulin (Ig)-A response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and taste and smell disorders.

Study: Long-term systemic and mucosal SARS-CoV-2 IgA response and its association with persistent smell and taste disorders. Image Credit: Huen Structure Bio / ShutterstockStudy: Long-term systemic and mucosal SARS-CoV-2 IgA response and its association with persistent smell and taste disorders. Image Credit: Huen Structure Bio / Shutterstock

The persistence of long-lasting coronavirus disease 2019 (COVID-19) symptoms (long-COVID) is a serious health concern among infected patients. Multiple organs and systems contribute to the extremely diverse clinical appearance. During the early COVID-19 pandemic phases, the incidence of olfactory and gustatory abnormalities with qualitative or quantitative modifications was notably high. The etiology of long-term COVID-19 is poorly known and may involve viral persistence or prolonged viral clearance, autoimmune, and inflammation-related tissue damage. Additionally, recent investigations have shown the durability of the humoral response against SARS-CoV-2. The potential of the mucosal humoral compartment in identifying prognostic indicators also needs thorough investigation.

About the study

In the present study, researchers explored the anti-SARS-CoV-2 IgA response over a year in the serum and saliva of moderate COVID-19 and uninfected controls.

The team chose 133 of the 400 volunteers who completed the whole longitudinal follow-up based on participant eligibility, the lack of a new SARS-CoV-2 infection at the time of follow-up, and the quantity/quality of their saliva samples. At each follow-up visit, the clinical state of the participants was assessed. The anti-SARS-CoV-2 IgA response was assessed in the blood and saliva of people with smell or taste problems that persisted either less or more than a year after acute infection with the SARS-CoV-2 Wuhan strain.

Results

At enrollment (V1), the team noted that the median symptom onset was 1.5 months. Specific IgA response against the SARS-CoV-2 spike was detected in nearly all previously infected persons' serum. The IgA antibodies specifically targeted the SARS-CoV-2 spike/receptor-binding domain (RBD) over the nucleocapsid (N) and Spike/N terminal domain (NTD). Compared to V1, the IgA signal reduced dramatically six months later (V2), independent of the targeted antigen. The mean anti-N IgA titer at six months decreased below the positive threshold. Anti-N IgA tended to drop between six and 12 months after cohort inclusion, with a negative modeling slope equivalent to a daily reduction of 0.21‰, whereas IgA titers elicited in response to all other targets remained stable.

Over time, the total Ig response against Spike/RBD rose while the total Ig response against the N declined. The serum seroneutralization activity against the SARS-CoV-2 BetaCoV/France/IDF0372/2020 strain was sustained for 16 months after infection. The correlation between seroneutralization titers at V1 and serum anti-Spike/NTD IgA was positive. Seroneutralization titers were linked with serum anti-spike IgA and serum anti-spike/NTD IgA levels more than six months after infection. More than a year following SARS-CoV-2 infection (V3) and in the absence of immunization, seroneutralization titers continued to correlate with anti-Spike IgA serum levels. Overall, the team found that the development of high anti-SARS-CoV-2 spike IgA serological titers was strongly linked with seroneutralization titers and was persistent for up to 16 months post-infection, despite an initial decline after six months.

At V1, unique anti-SARS-CoV-2 IgA was found in the saliva of infected persons, in contrast to the saliva of healthy individuals. These antibodies attacked the viral spike in its entirety, targeting the spike/RBD more than the spike/NTD, while the nucleocapsid was not targeted. In the initial six months, the amount of IgA in saliva reduced dramatically against all targets. Linear mixed models revealed negative slopes corresponding to a daily drop in IgA concentration for S by 1.16 ‰, spike/RBD by 0.89 ‰, and spike/NTD by 0.90 ‰. Between six and 12 months, a comparable decline against these viral targets was found.

After one year, a considerable number of COVID-19 patients had remarkable persistence of symptoms, particularly taste and smell problems. The team discovered that patients with persistent olfactory and gustatory deficits had higher anti-SARS-CoV-2 IgA titers at V1, which notably targeted the spike/NTD in the saliva samples but not the serum samples. Since spike-NTD specificity showed a positive correlation with higher seroneutralization titers, it may be a clinically relevant IgA target.

Conclusion

The study findings highlighted distinct kinetics and levels of IgA titer against the SARS-CoV-2 spike protein in the serum and saliva samples following infection, with the former persisting for up to 16 months after an initial drop while the latter disappeared after six months. The antigen specificity displayed by anti-SARS-CoV-2 IgA revealed the spike/NTD as a critical target, with favorable associations of anti-spike/NTD IgA serum levels with neutralizing antibody titers. Correlations were also noted between saliva anti-spike/NTD IgA levels and the long-term persistence of taste and smell problems.

As breakthrough infections have been found to be connected with IgA levels, IgA synthesis may be crucial in managing the infection locally and avoiding transfer from vaccinated persons. Therefore, future COVID-19 control will need the most effective vaccine platforms or routes of delivery eliciting mucosal immunity, as demonstrated in preclinical investigations.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Bhavana Kunkalikar

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.

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