CVR - Coronavirus Vaccines R&D Roadmap

Milestone
2.2.d

Biomarkers and surrogates

In progress
High priority

Determine mucosal biomarkers and the systemic surrogates that are predictive of mucosal immune protection against coronavirus infection, disease, and transmission.

Progress Highlights

See CVR Scholar Hub page: Known Mucosal Biomarkers for Coronavirus Immunity

SARS-CoV-2-specific secretory IgA (sIgA) in nasal and saliva secretions

Role: Neutralizes the virus at mucosal entry points, reducing viral load and transmission risk.

Systemic Surrogate: Elevated levels of SARS-CoV-2-specific serum IgA. However, circulating IgA lacks the secretory component and is often a “spillover” into mucosa, and has limited antiviral activity.

SARS-CoV-2-specific IgG in nasal and salivary secretions

Role: Reflects mucosal immune memory post-infection or vaccination.

Systemic Surrogate: Corresponding IgG levels in serum.

BAFF and APRIL cytokines

Role: Support activation of mucosal B cells and antibody class switching to IgA.

Systemic Surrogate: Elevated levels of BAFF and APRIL in serum promote B cell maturation and class switching to IgG.

IL-6, IL-8, IL-1β, and IFN-γ in mucosal secretions

Role: Enhance antiviral responses, particularly in the respiratory tract. High IFN-γ, IL-1β, and IL-8 in the mucosa is associated with mild disease.

Systemic Surrogate: Corresponding cytokine levels in serum. Note: Elevated serum IL-6, IL-8, IL-1β and others indicate a cytokine storm that correlates with organ damage. IFN-γ in the bloodstream is typically lower or delayed in severe cases.

Lymphoid chemokines (e.g. CXCL13, CCL19, and CCL21)

Role: Organize immune cell trafficking in tissues, and promote the formation of inducible bronchus-associated lymphoid tissues (iBALT), enhancing localized immune responses in the respiratory tract.

Systemic Surrogate: Elevated levels in serum can reflect ongoing germinal center reactions or severe infection driving extrafollicular responses.

IFN-λ (Type III Interferon)

Role: Induces antiviral states in mucosal tissues, enhancing innate immune defenses.

Systemic Surrogate: Serum levels of IFN-λ.

SARS-CoV-2-specific memory B cells in peripheral blood

Role: Indicate prior mucosal exposure and readiness for rapid antibody production upon reinfection.

Systemic Surrogate: Detectable SARS-CoV-2-specific memory B cells in blood samples.

Salivary vimentin

Role: Serves as a biomarker for mucosal immune activity and SARS-CoV-2 infection progression.

Systemic Surrogate: Unknown

Phospholipid Scramblase 1 (PLSCR1)

Role: Acts as a restriction factor that limits SARS-CoV-2 entry and replication in epithelial cells.

Systemic Surrogate: Upregulated PLSCR1 expression in peripheral blood cells has been linked to better viral control and milder disease.

CD8+ and CD4+ Tissue Resident Memory (TRM) T cells

Role: Recognize and eliminate infected cells in the nasal mucosa, contributing to localized immune protection. In lungs, presence of a robust lung TRM pool correlates with efficient viral clearance, milder symptoms, and long-term protection against severe disease.

Systemic Surrogate: Potential correlation with circulating T-cell subsets (e.g. CD69^ memory T cells), however correlation with nasal- and lung-resident T cells is unreliable.

Mucosal-associated invariant T (MAIT) cells

Role: Activate dendritic cells, promoting T follicular helper cell differentiation and subsequent humoral immunity. They also produce IL-17 and IFN-γ, contributing to the antiviral response.

Systemic Surrogate: Frequency and activation status of MAIT cells in peripheral blood. In moderate infection, circulating MAITs show an activated phenotype (CD38+ HLA-D+), correlating with mucosal defense, but in severe cases they exhibit signs of exhaustion (PD-1high) and functional impairment.