Intranasal Self-Adjuvanted Lipopeptide Vaccines Elicit High Antibody Titers and Strong Cellular Responses against SARS-CoV‑2

• Published in: ACS infectious diseases Vol. 10; no. 9; pp. 3419 - 3429
• Main Authors: Maxwell, Joshua W. C., Stockdale, Skye, Stewart, Erica L., Ashley, Caroline L., Smith, Lachlan J., Steain, Megan, Triccas, James A., Byrne, Scott N., Britton, Warwick J., Ashhurst, Anneliese S., Payne, Richard J.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.09.2024
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - pharmacology; Adjuvants, Vaccine - administration & dosage; Administration, Intranasal; Animals; Antibodies, Neutralizing - blood; Antibodies, Neutralizing - immunology; Antibodies, Viral - blood; Antibodies, Viral - immunology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; COVID-19 - immunology; COVID-19 - prevention & control; COVID-19 Vaccines - administration & dosage; COVID-19 Vaccines - immunology; Female; Humans; Immunity, Cellular; Lipopeptides - administration & dosage; Lipopeptides - immunology; Mice; Mice, Inbred BALB C; SARS-CoV-2 - immunology; Spike Glycoprotein, Coronavirus - immunology; Vaccines, Subunit - administration & dosage; Vaccines, Subunit - immunology; mucosal vaccine; solid-phase peptide synthesis; SARS-CoV-2; self-adjuvanted vaccine; peptide fusion vaccine; Pam2Cys
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.4c00544

Despite concerted efforts to tackle the COVID-19 pandemic, the persistent transmission of SARS-CoV-2 demands continued research into novel vaccination strategies to combat the virus. In light of this, intranasally administered peptide vaccines, particularly those conjugated to an immune adjuvant to afford so-called “self-adjuvanted vaccines”, remain underexplored. Here, we describe the synthesis and immunological evaluation of self-adjuvanting peptide vaccines derived from epitopes of the spike glycoprotein of SARS-CoV-2 covalently fused to the potent adjuvant, Pam2Cys, that targets toll-like receptor 2 (TLR2). When administered intranasally, these vaccines elicited a strong antigen-specific CD4+ and CD8+ T-cell response in the lungs as well as high titers of IgG and IgA specific to the native spike protein of SARS-CoV-2. Unfortunately, serum and lung fluid from mice immunized with these vaccines failed to inhibit viral entry in spike-expressing pseudovirus assays. Following this, we designed and synthesized fusion vaccines composed of the T-cell epitope discovered in this work, covalently fused to epitopes of the receptor-binding domain of the spike protein reported to be neutralizing. While antibodies elicited against these fusion vaccines were not neutralizing, the T-cell epitope retained its ability to stimulate strong antigen-specific CD4+ lymphocyte responses within the lungs. Given the Spike(883–909) region is still completely conserved in SARS-CoV-2 variants of concern and variants of interest, we envision the self-adjuvanting vaccine platform reported here may inform future vaccine efforts.