Mucosal Immunity in SARS-CoV-2 Vaccination

Mucosal immunity represents the first line of defence against respiratory pathogens by organising immune responses directly at the airway surfaces. Unlike systemic immunity, which relies predominantly on circulating antibodies and T cells, mucosal responses involve secretory immunoglobulin A (IgA), tissue-resident memory lymphocytes and innate barrier functions that together intercept virus at its portal of entry. In the context of SARS-CoV-2, eliciting robust mucosal immunity has emerged as a critical aim to reduce both disease severity and onward transmission. Intranasal or inhaled vaccine formulations seek to prime local antibody production and establish lung-resident T cells capable of rapid recall upon re-exposure. Such approaches may complement intramuscular mRNA or vector vaccines by filling gaps in sterilising immunity and by targeting emerging variants at the site of initial infection. Globally, mucosal vaccination strategies promise greater ease of administration, needle-free delivery and potential for self-administration, all of which could enhance uptake in low-resource settings and mitigate cold-chain dependencies.

Research from Nature Portfolio

Recent studies have shown that nasally delivered adenoviral-vectored vaccines encoding a prefusion-stabilised spike antigen induce high levels of mucosal IgA and cross-reactive CD8+ memory T cells in the respiratory tract. In murine and hamster models, this approach provided protection against both ancestral and antigenically distant Omicron strains, with CD8+ T cells critical to limiting lung infection when serum neutralising titres were low. Heterologous prime–mucosal boost regimens combining an initial systemic mRNA or DNA vaccine with an intranasal adenovirus boost have further demonstrated superior induction of lung-resident memory T cells and mucosal neutralisation of variants of concern compared to systemic booster alone. Foundational work with a single intranasal dose of a replication-defective human adenovirus serotype 5 vector expressing the SARS-CoV-2 spike protein confirmed protection in both upper and lower respiratory tracts of mice and ferrets, validating mucosal delivery as a potent means of achieving concurrent local and systemic immunity.

Mucosal Immunity in SARS-CoV-2 Vaccination publication trend

The graph below shows the total number of articles in mucosal immunity in sars-cov-2 vaccination across all publications each year (not limited to Nature Index journals).

Technical terms

Mucosal immunity: Immune defence mechanisms operating at mucosal surfaces, notably the respiratory and gastrointestinal tracts, that involve secretory antibodies, local T cells and innate effectors.

Secretory IgA (sIgA): A dimeric form of immunoglobulin A found in mucosal secretions, specialised for neutralising pathogens at epithelial barriers.

Tissue-resident memory T cells (TRM): Non-circulating T lymphocytes that reside long-term within peripheral tissues and provide rapid local recall responses upon antigen re-encounter.

Adenoviral vector: A genetically engineered, replication-defective virus used to deliver antigen-encoding genes to host cells, stimulating immune responses without productive infection.

Heterologous prime–boost: A vaccination strategy using distinct vaccine platforms for initial and subsequent doses to broaden and amplify immune responses.

Cross-reactive T cells: T lymphocytes capable of recognising and responding to related but antigenically variable strains of a pathogen.

References

1. Safety and efficacy of the intranasal spray SARS-CoV-2 vaccine dNS1-RBD: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Respiratory Medicine (2023).
2. Mucosal vaccine-induced cross-reactive CD8+ T cells protect against SARS-CoV-2 XBB.1.5 respiratory tract infection. Nature Immunology (2024).
3. A single dose of an adenovirus-vectored vaccine provides protection against SARS-CoV-2 challenge. Nature Communications (2020).
4. Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2. Cell (2022).
5. Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models. Science Translational Medicine (2021).
6. Protective mucosal immunity against SARS-CoV-2 after heterologous systemic prime-mucosal boost immunization. Nature Communications (2021).