tetano
Editor, Senior Moderator
Front Immunol
. 2024 Feb 2:15:1292059.
doi: 10.3389/fimmu.2024.1292059. eCollection 2024. A SARS-CoV-2 RBD vaccine fused to the chemokine MIP-3α elicits sustained murine antibody responses over 12 months and enhanced lung T-cell responses
James Tristan Gordy[SUP] #[/SUP][SUP] 1 [/SUP], Yinan Hui[SUP] #[/SUP][SUP] 1 [/SUP], Courtney Schill[SUP] 1 [/SUP], Tianyin Wang[SUP] 1 [/SUP], Fengyixin Chen[SUP] 1 [/SUP], Kaitlyn Fessler[SUP] 1 [/SUP], Jacob Meza[SUP] 1 [/SUP], Yangchen Li[SUP] 1 [/SUP], Alannah D Taylor[SUP] 1 [/SUP], Rowan E Bates[SUP] 1 [/SUP], Petros C Karakousis[SUP] 1 2 [/SUP], Andrew Pekosz[SUP] 1 [/SUP], Jaiprasath Sachithanandham[SUP] 1 [/SUP], Maggie Li[SUP] 1 [/SUP], Styliani Karanika[SUP] 2 [/SUP], Richard B Markham[SUP] 1 [/SUP]
Affiliations
Background: Previous studies have demonstrated enhanced efficacy of vaccine formulations that incorporate the chemokine macrophage inflammatory protein 3α (MIP-3α) to direct vaccine antigens to immature dendritic cells. To address the reduction in vaccine efficacy associated with a mutation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we have examined the ability of receptor-binding domain vaccines incorporating MIP-3α to sustain higher concentrations of antibody when administered intramuscularly (IM) and to more effectively elicit lung T-cell responses when administered intranasally (IN).
Methods: BALB/c mice aged 6-8 weeks were immunized intramuscularly or intranasally with DNA vaccine constructs consisting of the SARS-CoV-2 receptor-binding domain alone or fused to the chemokine MIP-3α. In a small-scale (n = 3/group) experiment, mice immunized IM with electroporation were followed up for serum antibody concentrations over a period of 1 year and for bronchoalveolar antibody levels at the termination of the study. Following IN immunization with unencapsulated plasmid DNA (n = 6/group), mice were evaluated at 11 weeks for serum antibody concentrations, quantities of T cells in the lungs, and IFN-γ- and TNF-α-expressing antigen-specific T cells in the lungs and spleen.
Results: At 12 months postprimary vaccination, recipients of the IM vaccine incorporating MIP-3α had significantly, approximately threefold, higher serum antibody concentrations than recipients of the vaccine not incorporating MIP-3α. The area-under-the-curve analyses of the 12-month observation interval demonstrated significantly greater antibody concentrations over time in recipients of the MIP-3α vaccine formulation. At 12 months postprimary immunization, only recipients of the fusion vaccine had concentrations of serum-neutralizing activity deemed to be effective. After intranasal immunization, only recipients of the MIP-3α vaccine formulations developed T-cell responses in the lungs significantly above those of PBS controls. Low levels of serum antibody responses were obtained following IN immunization.
Conclusion: Although requiring separate IM and IN immunizations for optimal immunization, incorporating MIP-3α in a SARS-CoV-2 vaccine construct demonstrated the potential of a stable and easily produced vaccine formulation to provide the extended antibody and T-cell responses that may be required for protection in the setting of emerging SARS-CoV-2 variants. Without electroporation, simple, uncoated plasmid DNA incorporating MIP-3α administered intranasally elicited lung T-cell responses.
Keywords: MIP-3α; SARS-CoV-2; T-cell response; antibody; dendritic cell; intranasal (IN); neutralizing antibody; vaccine.
. 2024 Feb 2:15:1292059.
doi: 10.3389/fimmu.2024.1292059. eCollection 2024. A SARS-CoV-2 RBD vaccine fused to the chemokine MIP-3α elicits sustained murine antibody responses over 12 months and enhanced lung T-cell responses
James Tristan Gordy[SUP] #[/SUP][SUP] 1 [/SUP], Yinan Hui[SUP] #[/SUP][SUP] 1 [/SUP], Courtney Schill[SUP] 1 [/SUP], Tianyin Wang[SUP] 1 [/SUP], Fengyixin Chen[SUP] 1 [/SUP], Kaitlyn Fessler[SUP] 1 [/SUP], Jacob Meza[SUP] 1 [/SUP], Yangchen Li[SUP] 1 [/SUP], Alannah D Taylor[SUP] 1 [/SUP], Rowan E Bates[SUP] 1 [/SUP], Petros C Karakousis[SUP] 1 2 [/SUP], Andrew Pekosz[SUP] 1 [/SUP], Jaiprasath Sachithanandham[SUP] 1 [/SUP], Maggie Li[SUP] 1 [/SUP], Styliani Karanika[SUP] 2 [/SUP], Richard B Markham[SUP] 1 [/SUP]
Affiliations
- PMID: 38370404
- PMCID: PMC10870766
- DOI: 10.3389/fimmu.2024.1292059
Background: Previous studies have demonstrated enhanced efficacy of vaccine formulations that incorporate the chemokine macrophage inflammatory protein 3α (MIP-3α) to direct vaccine antigens to immature dendritic cells. To address the reduction in vaccine efficacy associated with a mutation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we have examined the ability of receptor-binding domain vaccines incorporating MIP-3α to sustain higher concentrations of antibody when administered intramuscularly (IM) and to more effectively elicit lung T-cell responses when administered intranasally (IN).
Methods: BALB/c mice aged 6-8 weeks were immunized intramuscularly or intranasally with DNA vaccine constructs consisting of the SARS-CoV-2 receptor-binding domain alone or fused to the chemokine MIP-3α. In a small-scale (n = 3/group) experiment, mice immunized IM with electroporation were followed up for serum antibody concentrations over a period of 1 year and for bronchoalveolar antibody levels at the termination of the study. Following IN immunization with unencapsulated plasmid DNA (n = 6/group), mice were evaluated at 11 weeks for serum antibody concentrations, quantities of T cells in the lungs, and IFN-γ- and TNF-α-expressing antigen-specific T cells in the lungs and spleen.
Results: At 12 months postprimary vaccination, recipients of the IM vaccine incorporating MIP-3α had significantly, approximately threefold, higher serum antibody concentrations than recipients of the vaccine not incorporating MIP-3α. The area-under-the-curve analyses of the 12-month observation interval demonstrated significantly greater antibody concentrations over time in recipients of the MIP-3α vaccine formulation. At 12 months postprimary immunization, only recipients of the fusion vaccine had concentrations of serum-neutralizing activity deemed to be effective. After intranasal immunization, only recipients of the MIP-3α vaccine formulations developed T-cell responses in the lungs significantly above those of PBS controls. Low levels of serum antibody responses were obtained following IN immunization.
Conclusion: Although requiring separate IM and IN immunizations for optimal immunization, incorporating MIP-3α in a SARS-CoV-2 vaccine construct demonstrated the potential of a stable and easily produced vaccine formulation to provide the extended antibody and T-cell responses that may be required for protection in the setting of emerging SARS-CoV-2 variants. Without electroporation, simple, uncoated plasmid DNA incorporating MIP-3α administered intranasally elicited lung T-cell responses.
Keywords: MIP-3α; SARS-CoV-2; T-cell response; antibody; dendritic cell; intranasal (IN); neutralizing antibody; vaccine.