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JOURNAL OF MEDICINAL CHEMISTRY
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01642
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In this work, a new TLR4 agonist, GAP112, was synthesized as a potent adjuvant to enhance the immunogenicity of the SARS-CoV-2 spike RBD protein. The TLR4 agonist was conjugated to the protein antigen to create a liposomal formulation for vaccination. The conjugate vaccine significantly activated innate immune cells, induced a substantial increase in RBD-specific antibodies, and enhanced T-cell responses. Furthermore, the antibodies produced by the vaccine effectively neutralized SARS-CoV-2 variants.
Exploring potent adjuvants and new vaccine strategies is crucial for the development of protein vaccines. In this work, we synthesized a new TLR4 agonist, structurally simplified lipid A analogue GAP112, as a potent built-in adjuvant to improve the immunogenicity of SARS-CoV-2 spike RBD protein. The new TLR4 agonist GAP112 was site-selectively conjugated on the N-terminus of RBD to construct an adjuvant-protein conjugate vaccine in a liposomal formulation. It is the first time that a TLR4 agonist is site specifically and quantitatively conjugated to a protein antigen. Compared with an unconjugated mixture of GAP112/RBD, a two-dose immunization of the GAP112-RBD conjugate vaccine strongly activated innate immune cells, elicited a 223-fold increase in RBD-specific antibodies, and markedly enhanced T-cell responses. Antibodies induced by GAP112-RBD also effectively cross-neutralized SARS-CoV-2 variants (Delta/B.1.617.2 and Omicron/B.1.1.529). This conjugate strategy provides an effective method to greatly enhance the immunogenicity of antigen in protein vaccines against SARS-CoV-2 and other diseases.
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