Targeting the early life stages of SARS-CoV-2 using a multi-peptide conjugate vaccine.

The spike glycoprotein is a key factor in the infection cycle of SARS-CoV-2, as it mediates both receptor recognition and membrane fusion by the virus. Therefore, in this study, we aimed to design a multi-peptide conjugate vaccine against SARS-CoV-2, targeting the early stages of the virus's life cycle. We used iBoost technology, which is designed to induce immune responses against low- or non-immunogenic epitopes. We selected six peptide sequences, each representing a key domain of the spike protein (i.e., receptor binding domain (RBM), subdomain 1 (SD1), subdomain 2 (SD2), S1/S2, fusion peptide and the S2' sequences (FP + S2'), heptad repeat 1 (HR1)). Immunization studies in mice displayed targeted humoral and cellular immune responses against specific peptides of the spike protein simultaneously, while inducing cross-protection against the Delta and Omicron coronavirus variants. Moreover, vaccinated hamsters challenged with SARS-CoV-2 elicited high antibody levels against key peptides, induced early neutralizing antibody responses and resulted in less weight loss compared to controls. This highlights the potential for improving viral control and disease outcomes when utilizing this strategy. Therefore, by using iBoost technology in conjunction with our peptide design strategy, we were able to successfully target non-immunodominant regions in the spike protein while activating both arms of the adaptive immune system.