Challenges and considerations in multi-epitope vaccine design surrounding toll-like receptors

Epitope-based peptide vaccines elicit targeted immune responses, making them effective for diseases requiring focused immune activation, such as targeting cancer-associated antigens. Strategies like peptide cocktails and mRNA-based epitope vaccines have revolutionized the field; however, the term 'multi-epitope peptide vaccine' has been overextended, especially concerning the use of toll-like receptors (TLRs), their ligands, and peptide linkers. TLRs are often conflated with T cell receptors (TCRs) and B cell receptors (BCRs), which recognize immunogenic peptides within vaccines. This Opinion clarifies the role of TLRs and highlights challenges linked to their indiscriminate use in multi-epitope vaccine design. While peptide linkers are crucial in creating multivalent vaccines, their unsupervised application is increasing and warrants attention. After highlighting their role in advancing peptide vaccines, we discuss critical factors in linker implementation and caution against their misuse, which could undermine vaccines' efficacy.