Vaccines are needed that induce mucosal immunity against SARS-CoV-2

In a recently published study medRxiv* Preprint Server, UK researchers assessed assessed plasma and nasal antibody (Ab) responses induced after one year of hospitalization related to Coronavirus disease 2019 (COVID-19) and the potential boost from the subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations in the United Kingdom (UK).

Study: Nasal IgA decreases 9 months after hospitalization with COVID-19 and is not induced by subsequent vaccination. Credit: BINK0NTAN/Shutterstock

Studies have reported that mucosal immune responses prevent SARS-CoV-2 replication at the point of entry and reduce further virus transmission; However, data on mucosal humoral immunity and its correlation with systemic immune responses in COVID-19 convalescents are limited. In addition, research has reported on the potentiation of immune responses after vaccination; However, whether the immune enhancement is due to passive plasma Ab transfer to mucous membranes or whether COVID-19 vaccination can recall mucosal responses induced by SARS-CoV-2 infection requires further investigation.

Over time, SARS-CoV-2 has evolved with the emergence of several variants of concern (VOCs) with higher transmissibility and immune evasion. In particular, the Omicron variant and subvariants have shown reduced susceptibility to vaccine-induced immune responses. The immunity generated as a combined effect of SARS-CoV-2 infection and vaccination may enhance immunity against Omicron and other VOCs.

About the study

In the present multicenter, longitudinal study, researchers evaluated the durability of the mucosal immune response to severe COVID-19 and the additional benefit of subsequent COVID-19 vaccinations.

Clinical information, plasma and nasal samples were obtained prospectively from hospitalized adult COVID-19 patients (n=446) from February 2020 to March 2021 by the PHOSP-COVID and ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium 4C) consortia. Samples were collected during nine days of hospitalization and/or at intervals during convalescent periods (one month to 14 months after discharge).

Samples collected 6 months and 12 months after vaccination between September 2020 and March 2022 covered the start of the UK COVID-19 vaccination campaign and the severity of COVID-19 was assessed based on World Health Organization (WHO) clinical progression scores ) categorized. Immunoglobulin G (IgG) and IgA titers against SARS-CoV-2 nucleocapsid (NP), Spike (S) proteins of SARS-CoV-2 ancestral strain and Delta and Omicron BA.1 VOCs were measured evaluated by electrochemiluminescence analysis.

The results were correlated with those of pseudotype neutralization assays performed on plasma samples. In addition, the PubMed database was searched with search terms such as “nasal”, “mucosal”, “IgA”, “antibody”, “SARS-CoV-2”, “COVID-19”, “vaccination” and “convalescent” for relevant studies , published before July 20, 2022, in English.

As a result, three studies on the longevity of nasal down responses were analyzed, showing persistent nasal down response for three to nine months. However, the studies included patients with mild SARS-CoV-2 infections and small sample sizes. In addition, one study performed on home care subjects (n=107) showed increased salivary IgG titers after two mRNA (messenger ribonucleic acid) vaccinations, while another in SARS showed increased nasal IgG and IgA titers after seven to ten days of vaccination showed -CoV-2-exposed people.

Results

A total of 569 and 356 plasma and nasal samples were collected, of which 338 and 143, respectively, were collected from the same individual at different time intervals, and paired nasal and plasma samples collected at the same time point were available for 174 individuals. Robust nasal anti-NP and anti-S IgA titers were found within four weeks of symptom onset, decreasing by nine months.

Nasal IgA (A), nasal IgG (B), plasma IgA (C), and plasma IgG (D) responses to S of hereditary SARS-CoV-2, 12 months after symptom onset and compared to prepandemic controls (Gray) . Nasal IgA (E), nasal IgG (F), plasma IgA (G), and plasma IgG (H) responses to NP of hereditary SARS-CoV-2, 12 months after symptom onset and compared to prepandemic controls. The blue and red lines show the mean titer trend across each time point. The horizontal dashed line indicates the WHO cut-off for a seropositive titer. * = p<0.05, ** = p<0.01, *** = p<0.001, **** = p<0.0001.​​​​​​

In contrast, nasal and plasma anti-S-IgG titers that emerged within two weeks of symptom onset were persistently high for ≥ 1 year, with 2181-fold higher neutralizing plasma titers against all VOCs occurring at nine months vaccination were tested. The nasal IgG and IgA anti-S titers increased after ten months; however, only a 1.5-fold median change was observed for IgA alone, and anti-NP IgG and IgA responses remained low at nine months.

Two individuals developed reinfections (elevated anti-S and anti-NP IgG titers). Furthermore, in 33 subjects of known vaccination status, from whom pre- and post-vaccination samples were obtained, anti-S titers increased while anti-NP titers decreased. Most participants had been vaccinated between six months and one year after vaccination, which coincided with an increase in plasma and nasal IgG and IgA anti-S titers to all VOCs, although nasal IgA titers changed slightly.

No association was found between plasma IgG titers and nasal IgA titers among samples collected one year after hospitalization, suggesting that the humoral nasal IgA responses differed from the plasma responses and were minimally enhanced by vaccination . The decrease in nasal IgA titer after nine months of natural SARS-CoV-2 infection and the minor impact of COVID-19 vaccination could be due to the lack of long-term defense of the nasal mucosa against SARS-CoV-2 reinfection and the minimal Impact of vaccination on virus transmission. Infection-induced nasal Ab titers for VOCs circulating before Omicron showed binding to Omicron in vitro better than the one with plasma ab.

Overall, study results demonstrated sustained plasma and nasal IgG immune responses to SARS-CoV-2 B.1 strain, Delta VOC and Omicron VOC, which were enhanced by vaccination. However, nasal IgA titers did not correlate with plasma IgA titers, declined within nine months, and were not significantly enhanced by COVID-19 vaccinations. The results indicated that vaccination after natural SARS-CoV-2 infection was not able to adequately recall mucosal immune responses and underscored the need to develop vaccines that confer durable and robust mucosal immunity to Induce SARS-CoV-2.

*Important NOTE

medRxiv publishes preliminary scientific reports that have not been peer reviewed and therefore should not be relied upon as conclusive, guide clinical practice/health behavior, or be treated as established information.