Since the advent of immunization, vaccines have been composed of natural antigens pulled from the proteome of the infectious agent. To pick potentially protective antigens, pathogens must be deeply studied to elucidate their life cycles, patterns of protein expression, and interactions with their hosts. This reliance on understanding pathogen biology requires the etiology of disease to be known, hampers the speed of vaccine development, and generates vaccines with curtailed efficacy. Infectious pandemics and the cancer epidemic provide unambiguous motivation for the creation of an agnostic platform to develop potent vaccines.
Here, we outline our vaccine development approach to (1) characterize T-cell receptors (TCRs) responding to an insult, (2) perform antigen discovery for discovered TCRs, and (3) vaccinate with found, novel neoantigens. We hypothesize that novel, synthetic peptide ligands can effectively prime the same repertoire of na�ve T cells that clonally respond to infection. To find the optimal synthetic antigens, we designed a NFκB-driven, cell-based antigen discovery platform to interrogate TCRs with a diverse and streamlined pool of peptide antigens. Using our functional, unbiased method to screen for peptide ligands, we performed antigen discovery for known TCRs and novel TCRs from an in vivo cancer model. Our platform was specific, sensitive, and tunable in finding TCR-activating antigens. The system was able to successfully find cognate antigens for known TCRs. When performing antigen discovery for T cells resulting from an in vivo tumor model, our platform found antigens corresponding to known, expressed tumor antigens. Furthermore, we found that a streamlined peptide library can reduce peptide library complexity while still providing useful information on TCR-binding motifs. Our future directions include in vitro and in vivo testing with discovered neoantigens for known and novel TCRs.
Overall, identifying TCRs and screening TCR-binding ligands can aid in the development of vaccines in the fields of infection, cancer, allergy, autoimmunity, and transplantation. Our long-term goal is to bring about a new method for developing effective antigens for vaccines by identifying peptides that stimulate discovered, insult-specific protective T cells. If successful, our approach will have a major impact on vaccinology: we enable the possibility of developing effective vaccines without having to identify the insult as an initial step, a major boon for emerging infections or epidemics of known or unknown etiology.