CVR - Coronavirus Vaccines R&D Roadmap

Mucosal DCs release cytokines like IL-12 and IL-6 to promote Th1 and Th17 responses for antiviral defense and mucosal barrier integrity.

• Hu 2025: Thymic stromal lymphopoietin improves protective immunity of the SARS-CoV-2 subunit vaccine by inducing dendritic cell-dependent germinal center response
• Nasrollah 2023: Immune responses in mildly versus critically ill COVID-19 patients

Alqahtani 2024 found that DCs in the respiratory tract also help form inducible bronchus-associated lymphoid tissue (iBALT) by producing homeostatic chemokines (CCL19/21, CXCL13) that organize lymphocytes locally.

Cheang 2024 found that targeted DC vaccines or adjuvants can enhance DC function.

Recognize and kill infected cells that display stress-induced ligands or lack MHC-I expression.

Produce IFN-γ, amplifying antiviral defenses and enhancing T-cell responses.

• Balachandran 2024: NK cells modulate in vivo control of SARS-CoV-2 replication and suppression of lung damage
• Torcellan 2024: Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection
• Huot 2023: SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells
• Deng 2022: Exploring the utility of NK cells in COVID-19

SARS-CoV-2-specific CD8+ TRMs in the lungs and nasal tissues are critical for long-term immunity and reduced viral spread.

• Mukesh 2025: Intranasal booster induces durable mucosal immunity against SARS-CoV-2 in mice
• Yao 2025: ScRNA-Seq reveals T cell immunity in COVID-19 patients and implications for immunotherapy
• Zhu 2025: Robust mucosal SARS-CoV-2-specific T cells effectively combat COVID-19 and establish polyfunctional resident memory in patient lungs
• Gagne 2024: Mucosal adenovirus vaccine boosting elicits IgA and durably prevents XBB.1.16 infection in nonhuman primates
• Odle 2024: Tissue-resident memory T cells contribute to protection against heterologous SARS-CoV-2 challenge
• Ramirez 2024: Immunological memory diversity in the human upper airway
• Diallo 2023: Intranasal COVID-19 vaccine induces respiratory memory T cells and protects K18-hACE mice against SARS-CoV-2 infection
• Mitsi 2023: Respiratory mucosal immune memory to SARS-CoV-2 after infection and vaccination
• Roukens 2022: Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2-specific CD8⁺ T cell responses following COVID-19
• Lapuente 2021: Protective mucosal immunity against SARS-CoV-2 after heterologous systemic prime-mucosal boost immunization

Interferon-expressing T cells (especially IFN-γ)  inhibit SARS-CoV-2 infection and transmission.

• Eser 2023: Nucleocapsid-specific T cell responses associate with control of SARS-CoV-2 in the upper airways before seroconversion
• Nchioua 2023: Reduced replication but increased interferon resistance of SARS-CoV-2 Omicron BA.1

Yao 2025 found that TRMs are reduced in severe cases; TRM and CXCR6+ cells associate with protection.

CD4+ T cells

Th1 cells: Reduced in severe cases; imbalance of pro- and anti-inflammatory responses.

CD4-CTLs: Enriched in hospitalized patients; contribute to viral clearance and possibly immunopathology.

Tfh cells: Cytotoxic Tfh (GZMB+, PRF1+) expand in severe cases and may impair B cell responses.

Treg cells: Decreased in mild/moderate cases, increased and hyperactivated in severe cases (ENTPD1+, FOXP3+).

• Yao 2025: ScRNA-Seq reveals T cell immunity in COVID-19 patients and implications for immunotherapy

CD8+ T cells

Effector CD8+ T cells (GNLY+, GZMK+): Show cytotoxicity but also exhaustion in severe cases.

Exhausted CD8+ T cells express PD-1, LAG3, CTLA4; higher exhaustion linked to severe disease and poor outcomes.

• Yao 2025: ScRNA-Seq reveals T cell immunity in COVID-19 patients and implications for immunotherapy
• Zhu 2025: Robust mucosal SARS-CoV-2-specific T cells effectively combat COVID-19 and establish polyfunctional resident memory in patient lungs

Lim 2025 found that nasal SARS-CoV-2-specific T cells are detectable ≤3 months after infection but wane to near/below detection >3 months, while blood responses persist longer. Nasal CD8⁺ T cells further differed from in the blood by exhibiting NK-associated genes (KLRC1/2) and an absence of TCF7/TCF-1 and EOMES, implying limited self-renewal capacity.

NKT cells and γδ T cells

CD56+ and CD160+ subsets expand in moderate disease; Tim-3+ NKT cells associate with severity.

Reduced in blood but enriched in lungs; produce inflammatory cytokines (IFN-γ, IL-17, TNF-α).

• Yao 2025: ScRNA-Seq reveals T cell immunity in COVID-19 patients and implications for immunotherapy

Mucosal-associated invariant T cells (MAIT cells) 

Activate dendritic cells, promoting differentiation of Tfh cells that support robust humoral immunity .

Depleted in severe cases.

Increased IFN response.

• Yao 2025: ScRNA-Seq reveals T cell immunity in COVID-19 patients and implications for immunotherapy
• Amini 2024: Role of mucosal-associated invariant T cells in coronavirus disease 2019 vaccine immunogenicity
• Kammann 2024: Dynamic MAIT cell recovery after severe COVID-19 is transient with signs of heterogeneous functional anomalies
• Pankhurst 2023: MAIT cells activate dendritic cells to promote T_FH cell differentiation and induce humoral immunity