Before licensure, the clinical testing of vaccine candidates consists of three phases aimed at evaluating safety, immunogenicity and efficacy. In particular, phase I typically involves dose-escalation studies comparing a range of vaccine doses in people who receive the same dose of the vaccine during the prime and the boost. However, vaccine trials do not typically evaluate “intra-group dose escalation”, in which individuals would first receive a prime with a low dose and then a boost with a higher dose. Here, we performed studies in mice to determine the immunological effects of intra-group dose escalation. We first primed mice with a low dose or a standard dose of an Ad5-based COVID-19 vaccine, followed by homologous boosting with a standard dose to measure anamnestic immune responses. Our data show that limiting the priming dose of Ad5-vectored vaccines improves the boosting capacity of CD8+ T cell responses and antibody responses. This beneficial effect of limiting the priming dose was associated with reduced generation of vector-specific immune responses, as well as cell-intrinsic differences in memory T cell differentiation.
We thank Drs. Susan Weiss, Stanley Perlman, and Thomas Gallagher for discussions.
FUNDING: This work was possible with a grant from the Emerging and Re-Emerging Pathogens Program (EREPP) at Northwestern University, and a grant from the National Institute on Drug Abuse (NIDA, DP2DA051912) to P.P.M.
AUTHOR CONTRIBUTIONS: P.P.M., S.S., N.P., T.D., and T.C. designed and conducted the experiments. P.P.M. wrote the manuscript with feedback from all authors.
COMPETING INTERESTS: Pablo Penaloza-MacMaster reports being Task Force Advisor to the Illinois Department of Public Health (IDPH) on SARS-CoV-2 vaccine approval and implementation in the state of Illinois. Pablo Penaloza-MacMaster is also member of the Northwestern COVID-19 Vaccine Communication and Evaluation Network (CoVAXCEN) at Northwestern University’s Institute for Global Health.
DATA AND MATERIALS AVAILABILITY: RNA and TCR sequencing data are available in the Gene Expression Omnibus under accession number GSE173567. All other data needed to evaluate the conclusions in the paper and present in the paper or the Supplementary Materials.